Rhinosinusitis Current Concepts
Chronic Sinus Infection Thought to be Tissue Issue, Mayo Clinic Scientists Show It's Snot
Findings call for radical change in treatment for the disease, researchers say
VIDEO ALERT: Sound bites from a subject expert are available through Pathfire's Digital Media Gateway (DMG). See end of this release for details.
ROCHESTER, Minn. -- Mayo Clinic researchers have found that the cause of chronic sinus infections lies in the nasal mucus -- the snot -- not in the nasal and sinus tissue targeted by standard treatment. The findings will be published in the August issue of Journal of Allergy and Clinical Immunology and are available online.
"This strikingly teaches against what has been thought worldwide about the origin of chronic sinus infection: that inflammatory cells break down, releasing toxic proteins into the diseased airway tissue," says lead researcher and Mayo Clinic ear, nose and throat specialist Jens Ponikau, M.D. "Instead we found that these toxic proteins are released into the mucus, and not in the tissue. Therefore, scientists might need to take not only the tissue but also the mucus into account when trying to understand what causes chronic sinus infections and probably other airway diseases."
The findings could significantly change the way chronic sinus infection is treated, according to Dr. Ponikau.
"This has far-reaching implications," says Dr. Ponikau. "This suggests a beneficial effect in treatments that target primarily the underlying and presumably damage-inflicting nasal and sinus membrane inflammation, instead of the secondary bacterial infection that has been the primary target of treatments for the disease. Also, some surgeons have already started to change the way they do surgery for patients with chronic sinus infections, focusing now on removing the mucus, which is loaded with toxins from the inflammatory cells, rather than the tissue during surgery. Leaving the mucus behind might predispose patients for early recurrence of the chronic sinus infection."
Dr. Ponikau conducted this research along with Hirohito Kita, M.D., and Gail Kephart, Mayo Clinic allergic diseases researchers. David Sherris, M.D., and Eugene Kern, M.D., both former Mayo Clinic ear, nose and throat specialists who now work at the University at Buffalo, also participated in the project.
The team found that in chronic sinus infection patients, activated white blood cells (eosinophils) cluster in the nasal and sinus mucus and scatter a toxic protein (major basic protein) onto the nasal and sinus membrane. While major basic protein was not distributed in the nasal and sinus tissue, the level of this protein in the mucus of chronic sinus infection patients far exceeded that needed to damage the nasal and sinus membranes and make them more susceptible to infections such as chronic sinus infection.
To conduct this investigation, Dr. Ponikau and fellow researchers collected specimens from 22 consecutive Mayo Clinic chronic sinus infection patients undergoing endoscopic sinus surgery. The surgeons extracted the maximum possible tissue and mucus during the sinus surgery. The surgeons also extracted tissue and mucus from healthy patients undergoing septoplasty, surgery to fix a deviated septum, for comparison with the specimens from the chronic sinus infection patients. Through various forms of laboratory examination of the tissue and attached mucus, the investigators observed an abundance of major basic protein throughout the nasal and sinus mucus in all 22 specimens, but not in the tissue.
Chronic sinus infection is one of the most common chronic diseases in the United States, affecting 32 million adults, according to the National Center of Health Statistics. Chronic sinus infection produces nose and sinus problems characterized by stuffy nose, loss of sense of smell, postnasal drip, nasal discharge, and head and face pain lasting three months or longer. It notably decreases the quality of patients' lives, impairing physical and social functioning, vitality and general health, according to the Mayo Clinic researchers.
New Study Shows Sinus Surgery Can Improve Chronic Fatigue
Washington, D.C. -- A review of published medical literature shows that a common sinus surgery can help people suffering from chronic fatigue caused by sinusitis. The results were presented at the seventh International Conference on Chronic Fatigue in Madison, Wisconsin.
"The entire body of available medical literature points to the same conclusion: functional endoscopic sinus surgery reduces the chronic fatigue of sinusitis," said Alexander C. Chester, MD, clinical professor of medicine at Georgetown University Medical Center.
Chester analyzed the 11 available published scientific studies conducted on functional endoscopic sinus surgery in relieving fatigue. All 11 studies, including two from Harvard, demonstrated statistically significant decreased rates of fatigue post-surgery.
"Knowing there is a documented relationship between sinusitis and chronic fatigue, it seemed important to examine if sinus surgery can actually offer relief on the fatigue front," said Chester. "We need to explore the efficacy and viability of all available medical options to help those who suffer from debilitating fatigue."
The CDC approximates that 32 million people in the U.S. suffer from sinusitis; fatigue is a common symptom. For people who do not respond to medications as a treatment for their sinusitis, 80% remain fatigued, and out of these cases, fatigue is severe in over 20%. Because of persisting symptoms approximately 200,000 sinus surgeries are performed each year.
Functional endoscopic sinus surgery requires minimal cutting and is directed to a very localized area in the nose. Because the surgical area is so small, the recovery is much easier than nasal surgery of the past.
Although the procedure is expensive â€“ approximately ,000 including the in-patient hospitalization costs â€“ most is usually covered by insurance. Alternatively, recent studies in the Archives of Otolaryngology Head Neck Surgery and the American Journal of Rhinology show that the medical cost for a person with chronic sinusitis without surgery is per year which includes medications and physician visits. If job income loss is included, the annual cost soars to $1,539.
"In all 11 studies fatigue improved without exception and in many cases to levels considered normal," said Chester. "These findings appear universal, with similar reports noted in Germany and Turkey as well as the United States. The sustained benefits from endoscopic nasal sinus surgery suggest that it may be a worthwhile procedure for many patients with chronic sinusitis. People who are not getting better with medications alone should consult their ear, nose and throat doctor to consider alternatives including surgery."
Minimally Invasive Surgery Improves Symptoms of
Chronic Sinus Infection Sufferers
Procedure also helps reduce patient dependence on antibiotics, missed workdays and physician visits
BOSTON - Researchers from Brigham and Women’s Hospital (BWH) have found that patients who suffer from chronic rhinosinusitis (CRS), a long term viral or bacterial sinus infection, can find relief from symptoms which include nasal obstruction, discolored nasal drainage, loss of smell, facial pressure or pain, fatigue and headache, through endoscopic sinus surgery (ESS), a noninvasive outpatient procedure. In addition, study results suggested that ESS helps reduce dependence on antibiotics and antihistamines to mange these symptoms. These findings will be published in the March 2004 issue of The Archives of Otolaryngologyâ€“Head & Neck Surgery.
CRS is a debilitating form of sinusitis whose symptoms can lead to substantial physical and emotional impairment. According to the Sinus and Allergy Health Partnership (SAHP), approximately 31 million Americans are believed to have a sinus infection each year with approximately 20 million Americans experiencing CRS at some point during their lifetime. Sinusitis is more prevalent than arthritis and hypertension and, when chronic, sinusitis can be as equally debilitating as diabetes and chronic heart disease. In addition, according to the National Center for Health, Americans make 545,000 emergency department visits annually for CRS at significant costs to themselves. CRS sufferers have several treatment options but few that reduce symptoms to the same degree as ESS, a minimally invasive procedure that lasts approximately one to three hours with patients typically returning home that day. ESS allows a surgeon to delicately remove diseased tissue without having to make more radical facial incisions.
According to study’s lead researcher Neil Bhattacharyya, MD, division of Otolaryngology at BWH and assistant professor of Otology and Laryngology at Harvard Medical School (HMS), “Patients suffering from CRS symptoms experience a significant negative impact on their quality of life including missed days at work and medical costs associated with frequent treatments. This research demonstrates the clinical effectiveness of ESS to specifically address these symptoms allowing patients to take advantage of a straightforward, noninvasive medical procedure to reduce their symptoms to a point where medication dependence is lessened and quality of life is improved.”
In a nonrandomized clinical trial with 100 adult patients, researchers first conducted a rhinosinusitis symptom inventory, or a listing of the major and minor symptoms associated with CRS, within the study population. After following patients for an average of 19 months, researchers found that following ESS, patients experienced a statistically significant decrease in both major and minor symptoms associated with CRS as compared to the initial inventory. Specifically, researchers noted large size effects for reductions in facial pressure and nasal obstruction in addition to headache and fatigue. And, patients also demonstrated a 50 percent decrease in the number of workdays missed due to physician appointments. Findings also suggested that while use of topical nasal steroids did not appear to lessen after ESS, usage of antibiotics and antihistamines were reduced by 33 percent and 20 percent respectively.
“Prior to this study, the success of ESS to address individual symptoms such as facial pain, smell loss and fatigue, has been questioned, with many medical professionals believing that it provided only an incomplete relief of symptoms and, patients still experienced a high recurrence rate post-surgery,” Bhattacharyya said. “Clearly, this study provides compelling evidence that this may not be the case. Although ESS is not appropriate for every patient with CRS, if significant symptoms persist after appropriate medical treatment, CRS sufferers should talk to their physicians about surgical options that could help improve their quality of life as well as lessen their dependence on antibiotics.”
Rhinosinusitis affects 14% of the United States population (30 million people), at an estimated cost of .4 billion per year (3). In fact, rhinosinusitis (RS) is the medical condition most commonly reported to the U.S. Census Department (36).
Successful management of rhinosinusitis via medical and/or surgical avenues is achieved in the majority of patients, or symptoms resolve spontaneously. Surgery is typically reserved for those patients with CRS or recurrent acute RS who have not responded adequately to medical therapy, or in those cases where experience dictates the condition will most likely not respond adequately to non-surgical therapy, alone (e.g., invasive fungal RS, allergic fungal RS (AFRS), a subset of cystic fibrosis patients, anatomic abnormalities such as septal deviation or paradoxic middle turbinates, etc.).
Reported success rates based upon symptomatic improvement from Functional Endoscopic Sinus Surgery (FESS) range from 85%-92% (7). The group receiving most of the attention in the medical literature over the last 10 years is the 8-15% of surgical patients who have responded to neither medical therapy nor sinus surgery.
The present discussion will focus on 4 topics that have gained particular attention in the literature over the past 7 years: topical intranasal medications, immunodeficiencies in patients with refractory CRS, cystic fibrosis, and AFRS. These topics relate directly to that subset of patients that does not respond adequately to current medical and surgical treatments for RS.
Topical Intranasal Medications
Topical treatment for sinusitis has been increasing in popularity in part due to marketing by commercial interests. These treatments may be especially efficacious in those patients who continue to suffer from sinusitis despite adequate sinus surgery to open sinonasal communication. Topical saline solutions have been commonly applied in patients with rhinitis and sinusitis for years, but investigators have begun evaluating their effects on nasal physiology at a quickening pace.
Bactroban nasal is currently the only topical antimicrobial FDA approved specifically for use in the nose. A recent review of the literature spanning 53 years by Goh and Goode found that authors have reported the use of streptomycin, nitrofurazone, gentamicin, rifampicin, tobramycin, alpha-2 interferon, and amphotericin B in the nose for various reasons (17). However, little is known about how intranasal medications interact with and affect the nasal mucosa. Published reports have established that Lactated Ringers has no effect on ciliary beat frequency in vitro (6). However, the safety and efficacy of various saline solutions for nasal irrigation has been brought into question, and only recently have studies been performed to examine the effects that saline has on mucociliary clearance. Symptomatic relief from the use of various saline preparations has been reported by a number of authors over a period of decades (38). Talbot, et al., prospectively compared the effects of 3% saline and 0.9% saline on mucociliary clearance in 21 healthy patients serving as their own controls. They found a statistically significant improvement of 17% in the saccharin clearance time using the 3% solution, while no significant improvement in clearance was noted in the 0.9% group (38). Hypertonic solutions are thought to pull interstitial fluid from the nasal mucosa and therefore exert a mucolytic effect, which may explain this finding.
In contrast, Boek, et al., studied the effects of 0.9%, 7%, and 14.4% NaCl solution on human ciliary beat frequency in healthy mucosa in vitro. That group found complete and irreversible ciliostasis when 14.4% solution was used, complete and partially reversible ciliostasis when 7% solution was used, and a 54% reversible decrease in ciliary beat frequency when 0.9% solution was used. While hypertonic solutions may have a place in cystic fibrosis (due to mucolytic effects), lactated ringers would be a better choice for routine mechanical irrigation of the paranasal sinuses since it does not affect ciliary function. Even normal saline appeared to deleteriously affect the delicate intranasal mucosa (6).
An acidic milieu is thought to cause the “gel” state (more viscous) of mucus to predominate, whereas an alkaline milieu is thought to cause the “sol” state to predominate. This is the rationale for adding baking soda to saline irrigation solutions. However, no data is available to support this (38).
With respect to intranasal antimicrobials, even petrolatum-based intranasal medications such as bactroban have been reported to result in myospherulosis, lipoid pneumonia, and bronchiectasis. However, bactroban applied to the nasal vestibule is generally thought to be safe and effective in sterilizing the nares in Staphylococcus aureus carriers (17).
Elsewhere, various intranasal medications have been used with “success”: gentamicin (3.5 mg/side QD) in atrophic rhinitis, rifampicin in rhinoscleroma, alpha-2 interferon in colds caused by rhinovirus, and tobramycin in chronic rhinosinusitis (40 mg/side TID). However, the effects of these medications on the sinonasal mucosa and their therapeutic benefits are unproven. Their use at this time should be considered as a last resort until more information is available (17).
Immunodeficiency in Patients with Refractory Rhinosinusitis
There are more than 50 known immunodeficiency disorders. Immunodeficiency should be suspected in patients with recurrent acute RS that cannot be attributed to another underlying cause (anatomic obstruction, underlying mucociliary defect), a persistent infection that does not respond to adequate antibiotic therapy, infections at other sites (especially pneumonia, sepsis, and meningitis), unusual sinus pathogens or severe infections, or a family history of immunodeficiency (15).
The type of infection should guide the immunologic workup. Antibody deficiencies are associated with recurrent or persistent bacterial infections. T-cell deficiencies are associated with fungal, viral, and protozoal infections. Complement deficiencies are associated with gram-negative infections. Chronic granulomatous disease and leukocyte adhesion deficiency (both resulting from dysfunctional phagocytosis) are associated with infections from catalase-positive bacteria (e.g., Staph aureus), gram-negatives, and some fungi (15).
The most common immunodeficiency associated with chronic recurrent sinusitis is an IgG subclass deficiency. There are 4 IgG subclasses. IgG1 responds to bacterial protein antigens, and constitutes 67% of total serum IgG (IgG normal range 800-1800 mg/dL). IgG1 is tested functionally by a reaction to Tetanus and Diphtheria vaccinations.
IgG2 responds to bacterial polysaccharide capsules. It makes up 20-25% of total serum IgG. IgG2 can be tested functionally with the Haemophylus influenzae and Streptococcus pneumoniae vaccines.
IgG3 accounts for the most common subclass deficiency in adults. IgG3 responds to viral illness, Moraxella catarrhalis, and the M-component of Streptococcus pyogenes. The clinical importance of an IgG4 deficiency has not been elucidated (15).
Several authors have proposed guidelines for an “immunologic workup” (7,12,36). The workup should always start with a CBC with differential and an HIV test. Ig and IgG subclass concentrations should also be measured. In addition, IgG function should be assessed by the response to Diphtheria and/or Tetanus toxoid (protein antigens) and Pneumoccal vaccine (polysaccharide antigen), because the level of immunoglobulin could be normal but hypofunctional. A CH-50 test can be used to screen for complement deficiency when suspected. T-cell function can be tested in vitro (more sensitive) or in vivo based on delayed-type hypersensitivity to intradermal PPD or Candida.
The University of Iowa recently published a report examining the findings in 79 patients referred to the allergy and immunology clinic for persistent RS despite sinus surgery, or 3 episodes of acute sinusitis in the past year and no evidence of HIV, AFRS, CF, or primary ciliary dyskinesia. Workup included SET-testing, CBC with differential, quantitative IgG, IgA, IgM, and IgE (no IgG subclass), and T-cell function in selected patients. 53.3% had abnormal T-cell function (the most common abnormality encountered). 51% of patients had at least 1 positive result on SET. 29.2% had low IgE, 17.9% had low total IgG, 16.7% had low IgA, and 5% had low IgM. 19% of the original 79 patients were started on IVIG following their workup. This study suggested a high incidence of immune dysfunction in this population, and that T-cell dysfunction may play a significant role in hard-to-treat RS (7).
In an oft-cited paper by Sethi, et al., the authors examined 20 patients with CRS refractory to medical and surgical treatment found to have immunologic abnormalities. Results of the immunologic evaluation, which included IgG subclasses, stratified the subjects into 4 groups:
1. IgA deficiency in 8 patients
2. Ig deficiency with vaccine hyporesponsiveness in 5 patients (Common Variable Immunodeficiency, or CVID)
3. IgG1 deficiency, low IgG, and normal vaccine response in 4 patients (hypogammaglobulinemia)
4. IgG1 deficiency, normal IgG, and normal vaccine response in 3 patients.
Of note in this group was the incidence of CVID (25%); the incidence of CVID in the University of Iowa study was 9.9%. 9/20 (45%) patients in Sethi’s study were eligible for IVIG (7,36).
Success has been reported with the following treatment modalities (36):
1. IVIG ÃƒÂ¢Ã¢â€šÂ¬“ indicated for CVID, total IgG deficiency, and IgG subclass deficiency with a decreased response to vaccine (use of IVIG is controversial in patients with a subclass deficiency and a normal vaccine response); IVIG is NOT of benefit in IgA or complement deficiencies
2. Long-term antibiotic prophylaxis ÃƒÂ¢Ã¢â€šÂ¬“ Sethi reported good results with a regimen of Augmentin 500 mg QD
3. Genetic counseling/testing of other family members
Abnormalities in the CFTR gene have recently been implicated in chronic or recurrent sinusitis in otherwise healthy individuals. Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in Caucasians, with a prevalence of 1:2,000 live births in whites. The heterozygous carrier rate among Caucasians is 1:20-25. However, outside of the white population, cystic fibrosis is rare; incidence rates are 1:90,000 for Asians and 1:30,000 for African-Americans (31).
The hallmark of CF is thick, inspissated exocrine gland mucus 30-60 times more viscous than non-CF mucus that results in mucostasis and, in the sinonasal passages, obstruction. The mucociliary transport system is NOT directly affected, though cilia can be injured secondarily due to mechanical obstruction, inflammation, and infection (31).
The disease is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene on chromosome 7q31 coding for a chloride transport protein. In the most common mutation -- Delta-F508, which accounts for 70% of CF mutations ÃƒÂ¢Ã¢â€šÂ¬“ the CFTR protein fails to migrate to the cell membrane, remaining stuck in the cytoplasm. As a result, decreased chloride permeability leads to dessication of the extracellular fluid within the exocrine gland duct (15,31).
On a macroscopic level, this results in a multisystem disease characterized by chronic endobronchial infections, progressive obstructive pulmonary disease, pancreatic insufficiency (resulting in maldigestion), male infertility, and chronic rhinosinusitis with or without nasal polyposis. Cultures from respiratory tract discharge taken during infections in CF most often grow out Pseudomonas aeruginosa followed by Staphylococcus aureus. Death usually occurs secondary to renal failure or cor pulmonale (31).
The incidence of polyps in CF is 6-48%. Unlike allergic polyps, CF polyps display a relatively normal basement membrane, few eosinophils, and acidic rather than neutral mucin (31).
On presentation, CF patients often report minimal or no nasal symptoms, even in the face of massive disease by exam or CT scan; <10% of patients with CF report troubling nasal symptoms. This is thought to be due to the congenital nature of the disease (their noses have always been congested). The most common signs and symptoms, in descending order, are cough, nasal airway obstruction, rhinorrhea, and recurrent acute RS. 12% of patients report anosmia, though objective testing has revealed anosmia in 71% of the CF population (31).
The sweat test is the gold standard for diagnosis of CF (sweat chloride >60 mmol/L). This involves iontophoresis of pilocarpine into the skin at 5 mV for 5-10 minutes. All sweat must be collected from the same site. A negative sweat test in a patient highly suspicious for CF should be followed by a repeat sweat test and/or genetic testing. Of note, adrenal insufficiency, anorexia nervosa, hypothyroidism, and hypogammaglobulinemia are all capable of causing false positive sweat tests. The diagnosis of CF requires 2 positive sweat tests, or 1 positive sweat test and the identification of 2 CF mutations (15, 40).
Common findings on physical exam, aside from polyps, include broadening of the nasal bridge (36%), mouth breathing (34%), and medial bulging of the lateral nasal wall (12%). This medial bulging is associated with a mucocele-like phenomenon within the maxillary sinuses that also tends to displace the uncinate process from its usual position (31).
When CT is used to evaluate sinus disease in CF, it is extremely rare not to encounter sinus disease. Characteristic findings include a higher incidence of frontal sinus agenesis, medial bulging of the lateral nasal wall (63-100%), and impressive maxilloethmoid sinus opacification. Several authors recommend a sinus CT in every patient, at the very least as a baseline examination. If the patient is symptomatic, or bulging is noted on physical exam, this should be done immediately. Asymptomatic patients, particularly children, can wait until they are able to tolerate a CT scan without sedation (or until symptoms develop) (31).
Analogous to the relationship between sinonasal disease and asthma, patients with severe pulmonary involvement frequently improve significantly following sinus surgery (31).
The initial treatment for CF is medical, and includes antibiotics, intranasal steroids, buffered hypertonic nasal saline irrigation, short courses of systemic and topical decongestants, and steroid bursts. During evaluation, these patients should also be assessed for allergy, since the incidence is comparable to the incidence in the general population. Surgery results in significant improvement for CF patients. Indications for surgery include persistent nasal obstruction despite medical treatment, a medialized lateral nasal wall on physical exam or CT, pulmonary exacerbations that seem to correlate with sinonasal symptoms or worsening pulmonary status, facial pain or headaches affecting quality of life, and patient dissatisfaction with the results of medical management. Long-term, all CF patients should have regular “wellness” visits with an otolaryngologist (31).
The latest development with respect to CF is the role that CFTR mutations may play in the development of chronic rhinosinusitis in patients without a clinical diagnosis of CF. This could be a major development in the evaluation of RS given the high carrier rate of CFTR mutations in the Caucasian population. Wang, et al, performed a study comparing.147 white patients with CRS to 123 disease-free white patients with respect to the presence of CFTR mutations. They found 11 people in the CRS group (7.5%) with CFTR mutations, one of whom was ultimately diagnosed with CF by sweat test. Of note, 10 of these 11 patients were found to have double CFTR mutations. In the control group, 2 patients (1.63%) were found to have CFTR mutations (both single mutations). The odds ratio of CRS in CF carriers was 4.9 (though this did not achieve statistical significance). This study raises the possibility that certain double mutations in CFTR may result in significant epithelial dysfunction without producing outright CF (40).
A group from the University of Washington was the first to address the role that CFTR mutations play in rhinosinusitis in non-CF patients. They took sinonasal mucosa preserved from prior FESS cases and compared the distribution of CFTR proteins among non-CF children, CF children, and non-CF adults. With immunostaining, they determined whether CFTR was found primarily in the apical membrane, primarily in the cytoplasm, or mixed evenly. This was based on the fact that the delta-F508 mutation, and select other CFTR mutations, cause mistrafficking of the CFTR protein away from the apical membrane. They found that 73.7% of CFTR proteins were properly located in the apical membrane in non-CF adults requiring sinus surgery. In contrast 88.2% of CF children and 75% of non-CF children requiring sinus surgery had CTFR proteins located in either the cytoplasm or mixed between cytoplasm and membrane. This suggests that mutations causing mistrafficking of the CFTR protein may account, at least in part, for sinus disease severe enough to require surgery in children without a clinical diagnosis of CF (9).
Allergic Fungal Rhinosinusitis
Likely the hottest topic in rhinology, allergic fungal rhinosinusitis (AFRS) was first described by Safirstein in 1976; at that time, he referred to the entity as “allergic aspergillus sinusitis” and noted its similarity to allergic bronchopulmonary aspergillosis (ABPA). The pathophysiology of AFRS still is not clearly understood, and debate continues over just what AFRS is (26).
To begin, a brief overview of fungus is appropriate. Molds refer to fungi when present as hyphae (Confusingly, “mold” is also a term used generally by allergists to refer to fungal allergens). Yeasts refer to fungus when present as spores (spherical or ellipsoidal single cells measuring 3-15 micrometers in diameter). “Pseudohyphae” refer to budding spores that fail to detach, resulting in a chain of elongated yeast cells that mimics hyphae. Dimorphic fungi refer to fungi capable of growing as a yeast or a mold depending on environmental conditions. Cell wall polysaccharides and glycoproteins account for most fungal allergens. The dematiaceous fungi are a group of yeasts and molds with melanin in the cell wall, resulting in brown or black pigmentation. The dematiaceous fungi ÃƒÂ¢Ã¢â€šÂ¬“ the fungi most often associated with AFRS ÃƒÂ¢Ã¢â€šÂ¬“ include Bipolaris (the most common AFRS-associated species), Alternaria, Cladosporium, Curvularia, Drechslera, and Exserohilum. Aspergillus and Fusarium, in contrast, are hyaline molds (capable of producing toxins). Mucor and Rhizopus are Zygomycetes. Helminthosporium refers to a group of fungi that has since been broken down into 3 species: Bipolaris, Drechslera, and Exserohilum. Though there is no commercially available antigen for Bipolaris, Helminthosporium is commercially available (20,24,28).
AFRS is believed to account for 5-10% of chronic rhinosinusitis cases. It typically presents in adolescents and young adults (mean age 21.9 years). Most cases occur in warm, humid climates ÃƒÂ¢Ã¢â€šÂ¬“ particularly the Mississippi basin and the Southern United States ÃƒÂ¢Ã¢â€šÂ¬“ resulting in a marked variation in prevalence by region. Ferguson questioned 45 different otolaryngologists across the country in 2000, and found Memphis (23%) and Dallas (15%) to be the top two spots with respect to AFRS among chronic rhinosinusitis patients undergoing FESS.
Findings associated with AFRS include allergic rhinitis (67%), elevated specific IgE to at least 1 fungal antigen (90%), and asthma (50%). The typical presentation involves gradual nasal airway obstruction with semi-solid nasal crusts. As the disease progresses, extensive nasal polyposis develops, along with the development of sinusitis (unilateral in approximately Ãƒâ€šÃ‚Â½ of cases, and almost always one-side dominant). Pain is uncommon, and suggests concomitant bacterial sinusitis. The disease is typically recalcitrant despite medical and surgical therapy. Patients are generally unresponsive to antihistamines, intranasal steroids, and immunotherapy (before surgery). Systemic steroids often provide some relief, but relapse usually follows once the steroids are withdrawn.
As allergic mucin accumulates, the involved sinus begins to behave like a mucocele with bony remodeling and decalcification that can mimic invasion on CT scan. Proptosis, telecanthus, and intracranial extension without invasion can occur. Proptosis is particularly common in children with AFRS. The allergic mucin has a very characteristic appearance. It is thick, tenacious, and highly viscous. The color varies from light tan, to brown to dark green, and has been likened to peanut butter and/or axle grease. 75% of patients describe expelling darkly colored, rubbery nasal casts (20,26).
The characteristic mucin is the key to establishing the diagnosis of AFRS, and it is usually discovered at the time of surgery. Histologically, one sees branching , noninvasive fungal hyphae within sheets of eosinophils and Charcot-Leyden crystals. The Charcot-Leyden crystals consist of lysophospholipase. The hyphae are often sparsely scattered throughout the mucin; silver stains are helpful in visualizing the fungal elements, and the Fontana-Masson stain is particularly good at distinguishing Dematiaceous fungi. Meanwhile, fungal cultures are unreliable; a negative culture does not rule out AFRS, nor does a positive culture rule in AFRS. In fact, fungi are most likely present in most non-diseased noses. Of note, histologic examination of the sinonasal mucosa is not important for the diagnosis, but should be done to rule out invasion (20,26,33).
CT findings are very characteristic, with areas of high attenuation within expanded sinuses thought to represent proteinaceous allergic mucin, and hyperdense areas representing the accumulation of heavy metals and calcium salts within the allergic mucin. Bony erosion is very common (up to 98% of scans), but the dura and periorbita are NOT invaded. On MRI one sees central hypointensity on T1 and central signal void on T2 with increased peripheral T1 and T2 enhancement (20,25,26).
Beyond imaging , further workup includes total serum IgE and SET testing for both fungal and nonfungal antigens. Total IgE is typically >1,000 U/ml prior to treatment, and may be followed as an indicator of clinical activity during treatment (26).
Most authors cite some variation of the 5 Bent and Kuhn criteria (1994) for the diagnosis of AFRS:
1) Type-I Hypersensitivity confirmed by history, skin tests, or serology
2) Nasal polyposis
3) Characteristic computed tomography signs
4) Eosinophilic mucus without fungal invasion into sinus tissue
5) Positive fungal stain of sinus contents removed during surgery (and/or positive fungal culture) (5)
Treatment for AFRS has progressed significantly since the 1970’s. Initially, it was treated much like invasive fungal sinusitis, with wide debridement of the involved sinuses. Much of this had to do with the frightening appearances AFRS can have on imaging. This approach resulted in high morbidity and was still plagued by frequent disease recurrence (26).
More recently, treatment attacks the disease on three fronts: immunotherapy for atopy, FESS (and antifungal medications) to remove the fungal antigenic burden, and corticosteroids (topical and systemic) to halt the inflammatory cascade. However, even with maximal medical and surgical therapy, disease recidivism is the norm, making long-term followup essential (26).
Surgery is the cornerstone of treatment. Polyposis tends to result in bleeding and distortion of sinonasal anatomy. However, the polyps and mucin also tend to expand the sinonasal passages, facilitating access to normally hard-to-reach areas. In addition, one can “follow polyps to the disease”, since the mucin is typically trapped behind polyps. The goals of surgery are threefold: complete extirpation of all allergic mucin and fungal debris, permanent drainage and ventilation for the affected sinuses while maintaining intact mucosa, and post-operative access to the previously diseased areas. Postoperatively, encephaloceles are a concern because removal of large polyps in the setting of bony skull base erosion can result in prolapse of intracranial contents into the nose (25,26).
Most authors recommend systemic steroids before surgery, typically 40-60 mg prednisone per day for the week leading up to surgery (postoperative recommendations are more variable) (21,26). Post-operatively, patients should perform nasal irrigation with frequent (e.g., weekly) clinic visits for debridement.
Children with AFRS are treated differently from adults in that revision surgery is clearly preferred to prolonged systemic steroid usage (20).
Both systemic and topical steroids are important in preventing the recurrence of disease. INS should be part of the standard post-operative treatment. However, they tend not to be as effective preoperatively because of restricted nasal access. Systemic steroids have proven effective in decreasing recurrence rates of disease, but morbidity associated with long-term steroid use is high. Part of the aim of medical and surgical treatment in AFRS should be to minimize the dependence on systemic steroids (13).
Immunotherapy has been controversial in the treatment of AFRS; Ferguson reported in her experience that patients either worsened or did not improve when receiving immunotherapy preoperatively (13). However, Mabry published some promising results with immunotherapy when administered postoperatively, showing no recurrence after 4.5 years (24). The thought is that immunotherapy is not effective in AFRS until after the fungal (antigenic load) has been removed; preoperatively, immunotherapy can increase the level of IgG, which, in turn, could intensify a Type III hypersensitivity reaction. SET or RAST may be performed before or after surgery; the optimal timing for initiation of immunotherapy is thought to be 4-6 weeks postoperatively. Of interest, it is unclear how immunotherapy works in the case of AFRS, because the concentration of fungal-specific IgE has not been found to decrease in these patients, nor has the concentration of IgG or fungal-specific IgG (blocking antibodies) been found to increase. SET testing should involve a wide variety of fungal and non-fungal antigens. Of note, most AFRS patients tend to respond to multiple fungal antigens; an 18 kD protein has been found to exist common to multiple fungi, and there is some speculation that this may represent a fungal pan-antigen (20).
There is even less agreement regarding antifungal medications. Oral itraconazole has proven safe and may be somewhat effective (causing decreases in prednisone requirements and total serum IgE of approximately 80% when used for greater than 2 months). However, the cost of a 3 month course is approximately . There is currently no data regarding the use of topical antifungals and, again, the safety of intranasal topical antifungals is unknown (13).
In a 1996 review of 263 patients, Manning found that Dematiaceous fungi accounted for 87% of positive fungal cultures (Bipolaris being the most common); Aspergillus accounted for the remaining 13%. In 1997, Feger found Eosinophilic Cationic Protein present in much higher concentrations in AFRS mucin as compared to controls (suggesting an important role for eosinophils in the disease). In 1998, Manning and Holman examined a cohort of 8 patients with AFRS and found they all had Bipolaris-specific IgE and IgG, as well as a positive skin reaction to Bipolaris (26).
All of these findings supported what has become the working explanation of AFRS first proposed by Manning in 1989. AFRS, treated as a nasal correlate of ABPA (first described by Hinson in 1952), requires that an atopic host be exposed to fungi (the antigenic stimulus). Type I (IgE) and Type III (IgG immune complex) reactions occur, resulting in an intense eosinophilic inflammatory response. Inflammation, in turn, results in obstruction of the sinus ostia, which, in turn, results in stasis, which, in turn, results in further proliferation of fungus, which results in increased antigen burden, which results in a vicious cycle with the accumulation of copious allergic mucin (13,20,26).
However, Ponikau, et al., forced everyone to take a second look at the proposed mechanism of disease in AFRS. This group used a highly efficient method of collecting mucin and culturing for fungus. They cultured 210 people with chronic rhinosinusitis(CRS), and compared them to 14 asymptomatic patients with no inflammatory changes of the nasal mucosa. 96% of the CRS patients grew out fungus (an average of 2.7 species per subject). 100% of the healthy control group grew out fungus (an average of 2.3 species per subject). Of the 101 patients from the CRS group who underwent surgery, 93% met their criteria for the diagnosis of AFRS: CRS, the presence of allergic mucin, and the presence of fungal organisms within the mucin. “Allergic mucin” was based upon a histology of eosinophil-dominated mucus (gross appearance was not considered). Thus, their conclusion was that 93% of patients with CRS really have AFRS (33). It is important to note that this group disregarded atopy as a diagnostic criteria for AFRS. In addition, the study suggests an important role for eosinophils in CRS in general, which has been confirmed elsewhere. Furthermore, the presence of fungus in the nose (without a host predisposed to a dysregulated immune response) likely has very little clinical significance; this is not surprising, since the average male inhales 57,000,000 spores per day.(20).
However, Ponikau is not alone in questioning the role of atopy in AFRS. At this point, most agree that the disease is not caused directly by fungus in an immunocompromised host, but by otherwise harmless fungus in an immunologically “hypercompetent” host. Problems exist with the theory pointing to Type I and Type III hypersensitivity reactions. First, why would AFRS so often present unilaterally if it is a question of fungal-specific IgE in the serum? Second, immunotherapy does improve symptoms in AFRS, but it does so without affecting the levels of fungal-specific IgE. Third, IgG immune complexes, which have been found in ABPA patients, have not been found in AFRS patients (20).
The T-helper cell (TH-2 CD-4 cells) is another piece of the puzzle in AFRS that only recently has been discussed in the literature. These T-helper cells are prominent in IgE-mediated disease, are believed to play a role in the inflammatory cascade in ABPA, and release a variety of cytokines (IL-4, IL-5, IL-10, IL-13) which act directly to increase the number and activity of eosinophils and IgE. TH-2 activity is kept in check by TH-1 function, and vice-versa (20). Possibly the most promising theory to explain AFRS has come from Schubert, who refers not to allergic fungal sinusitis, but to “hypertrophic sinus disease” (HSD), minimizing the role that fungus plays in AFRS (merely a variant of HSD). All HSD is characterized by a nasal mucosa packed with eosinophils and plasma cells. He postulates that HSD is a disorder involving TH-2 activation, similar to asthma. Allergic/atopic patients have a TH-2 predominance, while non-allergic patients have a TH-1 predominance. He also notes that Staphylococcus aureus is also commonly cultured from AFRS patients. Certain S. aureus strains produce enterotoxins that can act as one of several known superantigens (other common ones being EBV and Rabies virus). Superantigens activate an inflammatory cascade by simultaneously binding HLA-II molecules on Antigen Presenting Cells and T-cell receptors on T-cells, thus bypassing classical antigen specificity. Superantigens are 3,000 times more potent at T-cell activation than classic, specific antigens. He postulates that enterotoxin-producing strains of S. aureus, dematiaceous fungi, and retroviruses may all act as superantigens which, in a host with TH-1/TH-2 dysregulation, can result in dramatic local or regional inflammatory responses resulting in HSD (35). The relationship between T-cell function and CRS is further bolstered by the recent report from the University of Iowa mentioned previously (7). As more work is done our understanding of the pathophysiology of CRS may change dramatically and radically alter our treatment of this troublesome problem.
Current Management of Nasal Polyposis:
Nasal polyps are the most common benign intranasal tumor. They are fluid filled sacs composed of an edematous tissue with infiltrating cells, including mast cells, eosinophils, lymphocytes and plasma cells surrounded by a ciliated airway epithelium.
The history of nasal polyps dates back over three thousand years to India where a type of currette was described for eradicating nasal polypi, "a frequent and troublesome disease in many parts of Hindustan." Hippoctrates is largely recognized as the father of Rhinology. His sponge method for polyp removal was included in textbooks as late as 19th century. Three strings were tied to a sponge cut to the proper size and shape. The other ends were fastened together and tied to a malleable probe, which was passed through the nose and into the pharynx. The ends of the strings were passed over a forked probe held in the pharynx. By placing traction, the sponge was forcibly dragged through the nose and pharynx, delivering the polyps with the sponge. Fallopius is credited with developing the snare, using a silver tube with an iron wire forming a loop at one end to engage the polyp. In 1571, Aranzi described using long forceps to forcibly grasp and remove polyps. This method remained popular in England until the early 19th century, being documented in lectures by Sir Astley Cooper. In 1882, Christopher Heath stressed environmental factors. He wrote, "The influence of the weather upon polypus nasi should be noted, damp causing them to increase largely in size." In 1922, the triad of nasal polyps, aspirin intolerance, and asthma was initially described by Widal.
Nasal polyps are seen in patients of all ages. They are present in approximately 2% of the population. There is at least a 2:1 male to female predominance. The frequency of nasal polyps increases with age, reaching a peak in individuals 50 years and older. Nasal polyps are not a disease, but a physical finding with a number of causes and associated conditions. Most commonly, 25%-30% of patients have asthma, while approximately 12 % have aspirin intolerance.
Nasal polyps are found in one-third of patients with aspirin intolerance and 7% of patients with asthma, and in 2% of patients with chronic rhinosinusitis. They are seen in 0.1% of children and in 20% of patients with cystic fibrosis. Any child under the age of 16 with nasal polyps should have a sweat chloride test as part of their evaluation. Nasal polyps are seen in 50% of the eosinophilic vasculitis of Churg Strauss Syndrome. The majority of patients with allergic fungal sinusitis have nasal polyps. They are also seen in disorders of ciliary motility like Kartagener's syndrome, as well as other genetic syndromes such as Young's syndrome, which is bronchopulmonary disease and azospermia.
As I mentioned, there is an association of nasal polyps with aspirin intolerance and asthma. These three factors together are know as Samter's syndrome or the aspirin triad. The prevalence is estimated to be 2%-3% in asthmatic patients in general and 20% of severe asthmatics. The typical patient is a middle-aged white individual with vasomotor rhinitis, perennial bronchial asthma, eosinophilia, negative skin tests to atopic allergens and an intolerance to aspirin and related chemicals. This reaction occurs within 15 to 180 minutes of ingestion and is marked by profuse rhinorrhea, often accompanied by macular erythema and/or nausea, vomiting, intestinal cramps, and diarrhea. An acute bronchial asthma attack ensues. Most patients recover from the acute reaction within 2 hours. Of course, not all patients present in this manner, and the syndrome usually develops over time. The asthma and aspirin intolerance generally develop within one year, with polyps forming up to ten years later. However, there is no greater incidence of positive allergy tests, and the male sex predilection disappears in this subset of patients, suggesting this may be a separate disease process.
All of this aside, the exact etiology of polyps remains unknown. Proposed mechanisms implicated in the development of nasal polyps include allergy, infection, autonomic imbalance, mucopolysaccharide abnormality, enzyme abnormality, drug sensitivity, mechanical obstruction, histamine, and proto-oncogene. The two major schools of thought are allergy and infection.
Before briefly entertaining these two theories, I would like to explore the histologic differences between nasal polyps and the normal nasal mucosa. Nasal polyps consist of respiratory epithelium covering a very edematous stroma infiltrated by a large number of inflammatory cells with eosinophils being the predominant cell. Eighty to ninety percent of polyps contain activated eosinophils. There are also increased goblet cells and areas of squamous metaplasia. Epithelial damage, in the form of an ulceration or desquamation, is another frequent finding. In addition the density of glands in nasal polyps is significantly less then normal turbinate mucosa with no true evidence of seromucinous glands. In addition to the increase in eosinophils and mast cells, there appears to be an up regulation of antigen presenting cells and immunocompetent cells such as B cells and lymphocytes.
The mast cells demonstrate ultrastructural signs of degranulation. Recent results have suggested that interleukins from activated CD4 T cells may play a role. There appears to be a continuous release of histamine, which is found in higher concentrations in polyp fluid. Gaps between endothelial cells of blood vessels allow passage of plasma into tissue. There is massive infiltration and activation of eosinophils with release of products that are cytotoxic and neurotoxic. Electron microscopy demonstrates a lack of innervation of surface epithelium, glands and blood vessels. Thus, these immature leaky blood vessels are devoid of normal vasomotor regulation. However, the specific trigger for this cascade of events remains unknown.
Allergy is suspected because of the predominance of eosinophils in nasal polyps. There is also the increased histamine levels and the presence of IgE. There is no significant difference in serum IgE levels, but researchers have shown increased IgE concentrations in polyp tissue. Mucosal mast cells are increased, but their degranulation does not appear to be IgE mediated. In addition, epidemiological data suggests that nasal polyposis occurs more commonly in non-atopic patients than atopic patients. As I mentioned earlier, nasal polyps are seen in 7% of asthmatics. This breaks down even further to 13% of non-atopic asthmatics vs. 5% of atopic asthmatics. Also, there is no increased incidence of allergies in patients who have nasal polyposis. The etiology may or may not be associated with allergy, but when the two conditions co-exist in the same patient, allergies can cause an exacerbation of nasal polyps.
Per Larsen and Mirko Tos published some interesting cadaver studies evaluating the origin of nasal polyps. They examined cadaver nasoethmoid complexes from autopsy specimens noted on anterior rhinoscopy to have polyps. Their goal was to evaluate if nasal polyps originated from either the nasal mucosa or anterior ethmoid air cells. They found that polyps originate from the nasal mucosa and were consistently related to sinus ostia. So, in theory, the osteomeatal part of the nasal mucosa is exposed to pathologic stimuli from the sinuses. This leads to polyp formation and begins a vicious cycle, leading to blockage of sinus ventilation and further polyp formation. This results in stagnant secretions and resultant infection. This infectious mechanism with stagnant secretions can be linked to polyp formation in Kartagener's Syndrome and cystic fibrosis. Additional support for an infectious etiology lies in the fact that intense antibiotic therapy against pseudomonas along with mucolytic therapy in these patients reduces polyp frequency to 2%-5%. In 1993, Norlander et al induced unilateral maxillary sinusitis in rabbits by blocking sinus ostia and injecting 3 different bacteria: pneumococcus, staph aureus, and bacteroides fragilis. Polyps were present in some 20% to 60% of the infected sinuses regardless of inciting pathogen. They were occasionally accompanied by polyp formation in the adjacent nasal mucosa. Histologically, deep mucosal trauma or epithelial desquamation seemed critical for polyp formation. But, as we all know, chronic sinusitis and hypertrophic mucosa are not always associated with nasal polyposis. Opacification of the paranasal sinuses can be seen in the absence of polyps in the nasal cavity.
The most common initial complaint of patients with nasal polyps is nasal obstruction. Other prominent symptoms include allergic complaints like watery rhinorrhea, sneezing, and itchy eyes. They may also complain of headache, asthma, or postnasal drip. Anosmia is another important symptom to ask about. Pain is usually present when an acute infection exists. Some may have middle ear pathology or rhinitis medicamentosa from chronic vasoconstrictor use. Many have had prior nasal surgery.
In severe cases, on physical examination, the nasal bones may be widened with polyps extruding from the nose. In other cases they can be visualized with a nasal speculum or an endoscope. They appear as smooth, gray, glossy lesions hanging from a narrow stalk. They are soft, mobile, and nontender to palpation. They are frequently multiple, bilateral, and vary in size. With the use of topical steroids, polyps may only be identified at the time of surgery with medialization of the middle turbinate. Other nasal abnormalities including septal deviation, condition of the nasal mucosa, and the presence of pathologic secretions should be noted.
CT scan should be used for evaluation of the paranasal sinuses in all cases. Coronal CT with bone windows is the standard x-ray study obtained. Review of the CT scan is done in a systematic approach with particular attention to the nasal septum, middle turbinates and bony sinus walls. There may be bony expansion and erosion. Air fluid levels and completely opacified sinuses should be noted. Attention should also be directed towards the density of the opacifications.
Although nasal polyps are the most common benign intranasal tumor, the differential diagnosis would include meningoceles or meningomyeloceles that may project through the nose via a cribriform plate defect or a dermoid cyst. Other benign possibilities include hemangiomas or angiofibromas. Other tumors including inverted papillomas, squamous cell carcinomas, and sarcomas can present with features similar to nasal polyposis. However, neoplasms are usually unilateral, friable, firm, and bleed spontaneously.
Before discussing medical and surgical treatment options, I want to briefly discuss means of assessing treatment efficacy. Symptom scores and presence of polyps on physical exam are two of the most common methods of measuring responses. Unfortunately, there is no rhinology equivalent of the pure tone audiogram to measure nasal obstruction, although both acoustic rhinometry and rhinomanometry have been used. Rhinomanometry is a technique for measuring nasal airway resistance. However, because more than 80% of the nasal airway resistance is produced in the valve area, and most polyps are behind that area, rhinomanometry is a rather insensitive method. Acoustic rhinometry is a volumetric method used to describe the geometry of the nasal cavity, which is based on the reflection of an acoustic signal entered into the nasal cavity. Other groups have studied the nasality of speech in healthy subjects versus those with nasal polyposis.
Treatment of nasal polyps revolves around medical and surgical management, or a combination of the two. The goals of medical management of nasal polyposis are to eliminate the polyps and rhinitis symptoms, to re-establish nasal breathing and olfaction, and to prevent recurrence without necessarily eliminating sinus pathology. Complete elimination of sinus pathology may be unrealistic, as many patients can be symptom free despite sinus opacification on their CT scan.
The mainstay of medical treatment is nasal steroids. On a cellular level, steroids bind to cytoplasmic glucocorticoid receptors and, within hours, they modify gene transcription inducing a change in cellular protein synthesis. There is evidence that the inflammatory reaction in asthma, allergic rhinitis, and nasal polyposis is in part driven by T lymphocytes and the cytokines products they produce. Cytokine production and activation is highly steroid sensitive. Studies have shown that topical steroids reduce the total number of T lymphocytes in nasal polyp tissue. Topical steroid therapy has not been shown to have any significant effect on the numbers of mast cells, but they do reduce the number of activated eosinophils. Polyps have leaky blood vessels, which result in an edematous stroma. Steroids have no direct effect on these leaky blood vessels, but they do have an indirect effect through inhibition of the formation of mediators and cytokines. As evidence of this anti-exudative effect, studies of nasal secretions following steroid therapy have shown a decreased albumin level. The clinical effects are manifest over several days.
Topically applied steroids have been studied in several controlled trials. Steroid therapy should at least improve nasal breathing. However, a patent airway is not necessarily a normal airway. Pressure from long standing nasal polyps may have widened the nasal cavity. This is a subjective symptom, and studies do support improvement in nasal breathing. More objective parameters like nasal peak flow and acoustic rhinometry have also demonstrated increases in nasal patency.
Topical steroids do reduce rhinitis symptoms by approximately 50%, but one must remember that these patients suffer predominantly from nasal obstruction with little sneezing and rhinorrhea. Studies do show that over 1-year, the anti- rhinitis effect is maintained and that symptoms slowly recur when treatment is discontinued.
Anosmia is a very annoying symptom for most patients. Clinical studies indicate that the response is poor especially when compared with systemic steroids, although controlled studies often pay little attention to this area. One recent study did show an improvement of 70%-80% of patients using a semiquantitative measurement, but also a 45% improvement in the placebo group. This difference was not statistically significant.
Several controlled studies document results ranging from reduction in polyp size to total polyp disappearance. However, polyps may not be completely eliminated from the upper part of the nose that cannot be reached by a nasal aerosol or spray. Reduction in size may make some patients symptom free, but small polyps still present in the upper nose may continue to compromise the osteomeatal complex and sense of smell. Thus, recurrence should be defined as polyps that can be identified by rhinoscopy and that are symptomatic. Studies have also looked at the effect of nasal steroids on the recurrence of polyps following surgical therapy, and this role of combined treatment will be dealt with shortly.
Adverse effects from nasal steroids are few and range from epistaxis to headaches and dizziness. There is minimal systemic absorption, and the dose is well below that required for adrenal suppression.
Lund et al, in May of 1998, performed a double blind randomized placebo controlled study of 34 patients with nasal polyposis scheduled for ESS. They demonstrated improvement in polyp scores and acoustic rhinometry versus placebo. Nasal obstruction scores also improved by almost 50% after 12 weeks of therapy.
Iin summary, recent studies have examined the effects of topical steroids versus placebo for anywhere from 4 to 26 weeks. They all document statistically significant improvements in subjective symptom scores and objective nasal flow rates. Symptoms can be controlled in anywhere from 50% up to 80% of patients. However, they do not abolish the need for surgical intervention. More study is warranted, especially examining in the area of cost effectiveness of medical treatment in delaying or preventing surgical therapy.
The benefit of systemic steroid treatment has been well documented, but routine use is often not recommended. Van Camp and Clement studied 25 patients with severe polyposis with no contraindications to systemic steroid therapy. These patients were treated with 4 days of 60mg of prednisolone followed by a gradual taper. Seventy-two percent showed subjective improvement with reduction in polyp size. Interestingly, only 52% displayed clear improvement radiographically. Those that did improve by CT scan were maintained on topical steroids. The majority recurred in 5 months. Those that did not improve by CT scan underwent endoscopic sinus surgery. They also note that pre-operative steroid therapy facilitated surgery. Contraindications to systemic therapy included glaucoma, diabetes, and prior tuberculosis. More relative contraindications include hypertension and peptic ulcer disease.
Surgery is an option for those patients whose quality of life is disrupted, who have failed an adequate trial of medical therapy, or who have a contraindication to some aspect of medical therapy. But, surgery is elective, and many feel should be considered as a part of a continuum of therapy and not independent of medical treatment. Surgical removal is not always a complete answer to the problem. The decision to intervene surgically may also depend on the presence of asthma, for which increasing steroid doses are required for control.
The spectrum of surgical treatment encompasses a variety of procedures ranging from snare and forcep polypectomy under local anesthesia to intranasal ethmoidectomy, total sphenoethmoidectomy, or functional endoscopic sinus surgery. For clarity, when I mention surgical therapy, I am referring to functional endoscopic surgery versus other more traditional techniques.
To aid in identifying normal landmarks, ESS usually begins with debulking of polyps as atraumatically as possible. This can be done with a snare, grasping forceps, laser, or a microdebrider. Once the polyps have been removed, the infected sinuses are approached and opened endoscopically. On exam the majority of patients have CT evidence of sinusitis in addition to nasal polyps. The extent of the procedure is variable and should be tailored to the patient's disease.
There have been several series that examine follow-up in patients with nasal polyposis after endoscopic sinus surgery. Study sizes vary from 100 to 250 patients with follow-up ranging from 18 months to 4 years. Determining patient satisfaction through relief of symptoms or examining the sinonasal area for the presence of disease usually assesses treatment outcomes. Studies show 80% -90% of patients reported symptom improvement with follow-up anywhere from one year to four years. These numbers are lower if one looks at patients that are completely symptom free. Others have also showed objective evidence of improvement in nasality of speech and unilateral reductions of airflow resistance.
Kennedy reviewed 120 patients undergoing endoscopic sinus surgery, of which 28% had diffuse polyposis and 31% had polyps arising from the middle meatus. He found the most important predictor of symptom improvement was the preoperative extent of disease. This may relate to the severity of underlying conditions like asthma and Samter's triad. Other researchers have noted that these patients tend to do worse. Also, patients with nasal polyposis who are surgical candidates tend to have more extensive disease involvement.
Despite excellent subjective improvement, many patients may have residual evidence of disease on endoscopic exam. Kennedy found the same degree of subjective symptomatic improvement in patients without polypoid disease, those with middle meatal polyposis, and those with diffuse polyposis. However, the endoscopic findings were vastly different. Seventy-seven percent of those patients without pre-operative polypoid disease had normal nasal cavities on follow up endoscopy at 18 months, while of those patients with diffuse polyposis, only 23% had normal nasal cavities on follow-up endoscopy. It is imperative to identify such early asymptomatic recurrence and to treat it medically or with local debridement before it becomes symptomatic.
Of course, ESS is not without complications, which include, among others, bleeding, orbital hematoma, CSF leak, and meningitis. The most common long-term complication of nasal polyp surgery is recurrence. Scahaitkin and May, in their follow-up of 100 patients for 4 years, noted a drop in success rates from 1- to 4-years, largely from patients with recurrent symptomatic polyposis.
Others have noted that nasal polyps are a symptom of systemic disease, the etiology of which is not altered by surgery. Therefore one should expect a higher rate of recurrence, especially with longer follow-up. Patients with recurrent polyposis compromise anywhere from 20%-40% of series of revision ESS. Perhaps control, rather than cure is a more realistic long-term goal.
The significant incidence of persistent disease highlights the need for continued topical steroid therapy. Anti-histamines and decongestants may improve a patient's symptoms, but they do not prevent recurrence. A number of studies have shown that long term post-operative treatment with topical steroids reduces the severity of recurrence. Patients who present for the first time and those with several years in between recurrences do not necessarily require post-operative treatment. A study by Hartwig et al from 1988, showed that in first time surgical patients, there was no significant effect in recurrence vs. placebo. They did confirm the benefit of post-operative topical steroids vs. placebo in those patients with recurrent nasal polyposis. However, those who had prior polypectomies had worse polyp scores with placebo than those maintained on nasal steroids.
There are no studies that clearly define when post-operative steroids should be started. The majority of studies do not specify this. Some comment that nasal steroids were begun in the post-operative period, while others wait until there is complete healing of the nasal cavities. There has been one study in which 20% of patients begun on post-operative topical steroids developed acute gram positive pan sinusitis. These patients started their topical steroid therapy after endoscopic demonstration of total epithelialization and absence of crustations for 10 days. They developed sinusitis approximately two weeks later.
As I mentioned earlier, treatment of nasal polyposis should involve a combination of medical and surgical management. Yet there have been a few studies that have pitted the two modalities against each other. Settipane et al studied 29 patients that underwent 49 surgical polypectomies with a recurrence rate of 1.7 and mean interval between recurrence of 6.3 years. Ten patients underwent 34 medical polypectomies or prednisone bursts with a recurrence rate of 3.4 and an interval of 0.9 years. Both groups were maintained on nasal steroids. Lilholdt et al randomized 53 patients to snare polypectomy versus an intramuscular steroid injection of Diprospan, a 2-cc suspension of betamethasone diproprionate and betamethasone disodium phosphate. Both groups received nasal steroids during the one year of observation. Both groups showed increases in mean nasal expiratory peak flows and olfaction. In general, the results in the two treatment arms were similar. Initial treatment was repeated in four patients in the medical group vs. three patients in the surgical group.
Surgical series consistently reveal poor control of nasal polyposis in patients with asthma, and this is even more pronounced in patients with the aspirin triad. These patients have increased recurrence rates and decreased control of symptoms. Earlier literature reported that polyp surgery would exacerbate asthma. Even Dr. Samter reported in 1958, that 10% of the 182 patients he studied had the onset of asthma within 9 months of polypectomy. However, research since that time does not support those claims. Series show that most patients showed improvement or at least were unchanged in the control of their asthma after surgery. Jankowski et al studied 50 patients who underwent a radical endoscopic ethmoidectomy. Thirty patients had asthma and 12 of those had aspirin intolerance. After 18 months, 91% of patients improved symptomatically. No patients had more than one asthma attack per week and 75% had fewer than four attacks per year. In addition, 25% were dependent on oral or injected steroids pre-operatively vs. only 8% post operatively. There were no cases of asthma in the control group of 20 patients with only nasal polyposis. There is a minimal risk of intra-operative bronchospasm. This incidence is higher during local anesthesia than general anesthesia.
Control of disease in this subset of patients is very challenging. Recent advances in medical therapy have involved the use of leukotriene inhibitors. Leukotrienes are products of arachidonic acid metabolism. Arachidonic acid is released from cell membrane phospholipids via the enzyme phospholipase A2. This substrate can be metabolized through one of two pathways. Aspirin inhibits the cyclo-oxygenase pathway. The other pathway is the 5 lipo-oxygenase pathway, which produces leukotrienes. Evidence for the role of leukotrienes in the pathogenesis of aspirin sensitivity lies in the fact that urinary leukotriene concentrations are increased after aspirin challenge. These patients also have increased target organ sensitivity to leukotrienes. Published studies support the use of leukotriene inhibitors in aspirin sensitive asthma. These drugs are effective in blocking aspirin-induced asthmatic responses. Their effect on nasal polyposis has yet to be studied.
In closing, I offer this quote from Dr. Mark May from the University of Pittsburgh:
"I'm an old doctor now, but I remember when I was a young doctor. We'd look in the nose with a headlight and speculum, or before electricity, with the reflected light of the sun, sometimes the moon. We saw this glistening stuff in the nose, and we had this little snare that somebody before us had designed. We reached in and pulled them out, and if we got a whole bunch of them, we thought we were doing well. We never really looked in the nose to see the position of the middle turbinate. Then steroids came along and made the polyps go away, but made the face round and the back humped up. It wasn't very good, and when you stopped the steroids, the polyps came back. Then CT scans came along, and we realized, 'Gee, these patients have pansinusitis. That's bad.' Based on the marked changes indicating pansinus involvement on CT scan, we began to think these patients were surgical candidates. It is interesting to note that some of these patients had few or no symptoms. Such a patient is not a surgical candidate. A symptomatic patient with massive polyposis who does not respond to intensive medical therapy and has persistent headache, fullness, and pressure, and postnasal discharge and can't sleep at night because of difficulty breathing often get immediate relief after surgery."
Nasal polyps are the most common benign intranasal tumor. They are associated with other disease states, and their exact etiology is unknown. Treatment revolves around a continuum of medicine and surgery with surgery being reserved for those with extensive disease that have failed adequate medical therapy. Treatment should be aimed toward control of the disease process.
FK is a 79-year-old female with a chronic history of bilateral nasal obstruction for several years. She had undergone one prior "polypectomy" several years ago in her native country. This procedure initially relieved her obstructive symptoms, however, her symptoms have worsened over the last year, despite treatment with nasal steroids. She also complained of anosmia and occasional postnasal drip. She denies any rhinorrhea, headache, asthma, or aspirin sensitivity.
Past medical history was positive for hypertension. Past surgical history as noted above. Her current medications included Flonase, Adalat, Clonidine, and Lorazepam. She had no known drug allergies.
On physical examination her ears and tympanic membranes were clear and intact bilaterally.
Anterior rhinoscopy revealed polyps present in both nares extending into the vestibule. There was mild erythema of the mucous membranes. Inferior turbinates could be visualized bilaterally. There were no purulent secretions noted. Oral cavity and oropharynx were clear. Her true vocal chords were mobile bilaterally. No neck lymphadenopathy or masses were observed.
Martin, the Virtual Nose Simulator, paves way for safer sinus surgery performances
New York 20 Jan 00 The N in ENT which stands for the ear, nose, and throat medical practice, may never become the same again when otolaryngologists start to incorporate Lockheed Martin's endoscopic sinus surgery simulator into their training regimens. The Akron business in Ohio has partnered with MedOps LLC to market the new tabletop device, selling its first commercial simulator to Montefiore Medical Center in the Bronx, New York, for use by its residents who started the initial testing in January. Each year, there are over 400.000 sinus surgeries performed in the United States, and more than fifteen million Americans are afflicted with chronic sinus ailments that this type of surgery could possibly remedy.
Learning how to perform high-risk sinus operations near the optic nerve and brain has become safer for patients because of virtual reality training techniques so lifelike that students can feel a scalpel cutting into nasal tissue. The otolaryngology residents at Montefiore Medical Center now practice on a software-driven mannequin and hand-held devices which allow to manoeuvre an endoscope, a number of scalpels and over a dozen other simulated surgical tools through the delicate interior anatomy of a virtual nose. Surgeons must recognise anatomy landmarks to ensure they do not probe too deeply up the passageway into the brain or sever arteries. From novice medical student to specialist, the new simulator presents ever more challenging training scenarios, as to inculcate users in the anatomy of the nose.
"The sinus surgery simulator is so real that you actually feel a rotating surgical tool as it cuts through a nasal tumour. Its level of sophistication is unprecedented", stated Marvin Fried, MD, who since 1998 is chairman of Otolaryngology at Montefiore Medical Center and Albert Einstein College of Medicine in New York City. Before, using cadavers was the standard method to train physicians in sinus surgery. But unlike with a cadaver, if a student makes a mistake, he or she can practice the complex operation over and over again, according to Dr. Fried. Dr. Fried also commented that sinus anatomy and surgery to correct physical conditions lend themselves fine to replicating with a simulator. The anatomy is very rigid, making its database modelling practical. The surgery is classified as high risk, so repetitive training might make a difference in surgical outcomes.
The software-driven mannequin can be utilised by students as they progress from novice over intermediate to advanced stages of surgical training. Also practising otolaryngologists who seek continuing education are able to apply the new technology. When performing a virtual operation, the parts of the anatomy can be labelled, for learning purposes, or left unlabelled. The nose surgery simulator utilises equipment similar to that of an actual operating suite, such as monitors for surgeons to view procedures within the sinus passageways, endoscope, an ever-expanding array of instruments, and a patient that keeps going and going. During sinus surgery, a surgeon inserts a camera-tipped endoscope, into a sinus passageway to view the procedure on a monitor as he works. Other instruments, including miniature forceps, needles and scalpels, are moved into the passageway to hold back, inject and remove tissue.
Martin, as the computer has been named, responds to voice commands such as: "Wake up Martin. Scissors." This request prompts a cartoon pair of scissors to appear inside the virtual anatomy of a nasal cavity shown on the monitor. Through a hand held device, the student is able to navigate the scissors through the three dimensional space to abnormal and infected tissue and remove it. And if, by any chance, the scissors, scalpels, or other instruments get too close to the eye, Martin calls out: "Warning. You have cut the lamina papyracea." This is the bone separating nasal and eye cavity. In order to ensure anatomical accuracy, the virtual patient model incorporates high-resolution digital images of human anatomy provided by the National Library of Medicine's Visible Human Project.
"Computers are not new in the operating room", stated Dr. Fried, who already earlier on has developed a navigational system for sinus surgery to help minimise the patient risk. "With this innovative training device though, technology takes a giant leap into the future. It can simulate fifteen separate surgical tools, it has tactile feedback so the surgeon actually feels the instrument working, it allows students to manoeuvre tools through a 3D virtual space which replicates the anatomy of the nose, and it allows to teach surgeons to operate on many different types of ailments. For example, you can tell the computer to create a foreign body or a polyp, which the student has to correct afterwards."
The majority of the over 250.000 endoscopic sinus surgery operations which are performed annually in the United States are done to relieve chronic sinus diseases involving nasal polyps, infections and tumours. These procedures are the highest risk operation which otolaryngologists have to perform. Each year 10.000 patients around the world are adversely affected as a result of a sinus surgery procedure. "If improved training reduces that number by 25 percent, the installation of simulators would be more than paid for and may encourage health care insurance providers to require such training of surgeons", stated Henry Grausz, MD, president of MedOps. The use of the simulator has major implications in surgical training, especially in areas of the world where operating on cadavers is forbidden. The innovative sinus surgery simulator, that has been used before in the U.S. Army hospitals, was created both by Lockheed Martin and MedOps, a Cambridge, Massachusetts, company.
Lockheed Martin developed the first endoscopic sinus surgery simulator in co-operation with Madigan Army Medical Center, Tacoma, Washington, and delivered it in 1997 to the Army. Since then, medical students and interns there have used the simulator as a hands-on training device. The company is readying another copy of the simulator for delivery in February to the U.S. Naval Medical Command in San Diego. "Our experience in designing high-fidelity training simulators for military aircraft has enabled us to solve the technical problems associated with real time simulation of the surgical procedures", commented Andrew Gurcak, Lockheed Martin medical simulation product manager.
Montefiore forms the test site for private non-profit teaching hospitals in the United States. "With 24 ENT residents at Montefiore and more than 120 specialists in the New York City area, Montefiore and the Albert Einstein College of Medicine provide an opportune stage for the commercial debut of this anatomy simulator", as Henry Grausz explained. The Montefiore Medical Center is internationally recognised as a leader in patient care, education, research and community service. It is the teaching hospital for the Albert Einstein College of Medicine, and encompasses two acute care hospitals, two new ambulatory speciality care centres, a network of more than 30 primary care offices in the Bronx and Westchester, and one of the United States' largest home health agencies.