Chronic rhinosinusitis (CRS) is defined as inflammatory disease of the sinuses that lasts for more than eight weeks; however, a specific etiology of this complex condition remains largely unknown. Fungus, biofilms, and superantigens, whether alone or in combination, are some of the many potential causes being explored, say experts. Other causes may include allergens, viruses, or genetic factors.
The disease is multifactorial and feeds into a common pathway that is not static and creates varying amounts of symptoms, said James Palmer, MD, Assistant Professor in the Division of Rhinology and Department of Otorhinolaryngology/Head and Neck Surgery at the University of Pennsylvania.
Theories surrounding the causes of CRS, whether airborne fungi, biofilms, or superantigens, all have their merits and downfalls, and researchers don’t know if any of these actually cause the condition, added Dr. Palmer. They are all threads of truth in a big tapestry picture of the disease, he said.
No research exists that allows investigators to completely exclude the idea that multiple factors contribute to the development of CRS, said Jens U. Ponikau, MD, Clinical Assistant Professor of Otolaryngology at the School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York (SUNY).
As scientists continue to develop a better understanding of CRS, they hope their research will one day affect treatment for the roughly 32 million cases of the condition reported to the Centers for Disease Control and Prevention annually.
Complexities of Chronic Inflammation
By definition, CRS is a disease of inflammation; however, inflammation is an extremely complex process, which makes determining disease etiology difficult, said Joel M. Bernstein, MD, PhD, Clinical Professor of Otolaryngology and Pediatrics at the School of Medicine and Biomedical Sciences at the University at Buffalo, SUNY.
Patients with CRS experience an infiltration of persistent inflammatory cells, which can include eosinophils, lymphocytes, mast cells, macrophages and fibroblasts, explained Dr. Bernstein. These cells produce inflammatory mediators in the sinuses leading to disease symptoms.
Researchers are trying to understand what factors feed this chronic inflammation, said Dr. Bernstein. Most people get an infection, which the immune response gets rid of, and then they get better, he said. But in patients with CRS, there’s obviously some sort of ongoing stimulus.
The patient’s immune system tries to fight off foreign offenders, whether fungi, allergens, or superantigens, and then remission occurs, he explained. However, these offenders are not completely eliminated, and consequently, the immune response starts all over again. The nose is not sterile, he said. There are always some bacterial or fungal factors, or toxins released by bacteria to keep the inflammation going.
To further complicate matters, anatomical factors may predispose the patient to CRS, and the disease can affect just one of the paranasal sinuses, a few at one time, or all of them, he added.
Most people get an infection, which the immune response gets rid of, and then they get better. But in patients with CRS, there’s obviously some sort of ongoing stimulus. – -Joel M. Bernstein, MD, PhD
An allergic reaction to fungal antigens may be one reason why patients develop CRS. It is likely that some patients have a sensitivity or allergy to fungi, and this leads to an immune response that results in chronic sinusitis, said Marilene Wang, MD, Professor in the Division of Head and Neck Surgery at the University of California at Los Angeles David Geffen School of Medicine.
Whether the fungi are actually infecting the sinus tissue in patients with allergic fungal sinusitis is unclear, she added. It is more likely that this is not a true infection [that] requires antifungal therapy, but rather an allergic or immune response to the fungi, she said.
A non-allergic muscinous eosinophilic form of CRS caused by fungi, which may respond to antifungal treatment, is being studied by Dr. Ponikau and his colleagues at the Mayo Clinic. Research indicates that fungi, specifically Alternaria, are present in CRS patients and healthy controls.
However, CRS patients, unlike controls, react with cytokine production, which is crucial for eosinophilic inflammation. The fascinating fact was that all the CRS patients were reacting but not healthy persons, said Dr. Ponikau of his research.
Eosinophils appear to target fungi in the paranasal mucus, explaining why these inflammatory cells appear in the sinuses, he said. One reason why determining CRS etiology has been challenging is because physicians did not appreciate the kind of inflammatory process underlying the disease, namely eosinophilic inflammation, said Dr. Ponikau.
Alternaria induces eosinophil degranulation, which means that the inflammatory cells release their toxic mediators, such as major basic protein, he explained. We have already found the actual antigen, meaning the substance coming out of the fungus, which the inflammatory cells react to, he said.
It is now possible to sensitize mice to fungi, which produces the same kind of eosinophilic inflammation resulting in CRS, he said.
We also found that lymphocytes regulate eosinophilic inflammation, he said. We can reproduce this disease process in the Petri dish, and we found that a signal coming from those lymphocytes is necessary to induce the attack of the eosinophils against the fungi. Lymphocytes from healthy people are lacking this signal; thus, eosinophils were not attacking the fungi.
Understanding the mechanisms behind eosinophilic inflammation will allow researchers to develop pharmaceutical interventions, said Dr. Ponikau. Researchers are identifying the antigens and the receptors on the eosinophilic cells and in the process are finding ways to block this abnormal immune response to the fungi, he explained.
Dr. Bernstein does not discount the non-allergic fungal CRS theory, but we have yet to see the last word on it yet, he said. Fungi are found in the noses of people without disease, so CRS may be a sign of an immune deviation in the patient, he explained.
Most otolaryngologists have found that fungi account for a small number of CNS cases, he added. In the southwestern part of the United States, where fungus growth is high, it may be responsible for 20% to 30% of disease, he said.
Researchers have put forth a hypothesis that fungus is the cause of most CRS, but I don’t think that’s realistic, said Dr. Palmer.
Large colonies of bacteria called biofilms may also play a role in CRS, according to Hassan Ramadan, MD, MSc, FACS, Professor and Vicechair of the Department of Otolaryngology Head and Neck at West Virginia University. He and his colleagues conducted a prospective study of the presence of biofilms in 30 patients undergoing endoscopic sinus surgery for CRS compared with four controls without the disease.
They found an 80% correlation between CRS and microscopic evidence of biofilms, said Dr. Ramadan. All controls had healthy-appearing cilia and goblet cells without biofilms. That only 80% of CRS subjects showed evidence of biofilms in their samples may be because of the collection technique of small samples not being representative of the entire sinonasal cavity, according to the study authors. It may also be that not all CRS patients have biofilms as the underlying etiology, they wrote. Bacteria may send out messages to other bacteria to form biofilms-large lattice-like colonies-in the sinuses, said Dr. Bernstein.
Biofilms have been discovered in many chronic infectious processes, including otitis media, periodontal disease, and sinusitis, said Dr. Wang. In addition, patients with CRS and polyps have been found to have biofilms. They are difficult to eradicate with systemic antibiotics, which may explain why some CRS patients don’t respond well to the medications, she said.
I do not question that biofilm is present, but I have not seen a single piece of evidence that the biofilm is actually causing the inflammation, said Dr. Ponikau. Many people do not understand that bacterial infection produces a neutrophilic inflammation, not an eosinophilic one. In addition, no one has been able to cause an eosinophilic inflammation with a bacterial infection.
Further research needs to be done about specific treatment modalities that could target biofilms in the sinuses, said Dr. Wang.
Additional studies also need to evaluate what makes the biofilm condition start and whether biofilms are the reservoir for superantigens and/or fungi, said Dr. Palmer.
A persistent bacterial infection may be a root cause of CRS, said Dr. Bernstein. He has been studying bacterial infections and the role of superantigens in the disease. Superantigens are defined as the exotoxins released by certain kinds of bacteria, including Staphylococcus aureus. Superantigens have special mechanisms that can upregulate lymphocytes, activating their Vbeta region, thereby producing TH1 and TH2 cytokines.
These cytokines bring inflammatory cells and eosinophils to the nasal mucosa, causing CRS. S. aureus is present in the mucin adjacent to nasal polyps in about 60% to 70% of cases of massive nasal polyposis.
Investigators have shown that superantigens are present in a certain percentage of patients, and that very severe patients produce IgE against these superantigens, which mediates to allergic rhinitis or allergy, but I have not seen any evidence that superantigens are stimulating the eosinophilic inflammation in CRS patients, said Dr. Ponikau. Superantigens might turn out to be an exacerbation factor-meaning that they fuel the fire-but so far much evidence is missing, he said.
These toxins released by S. aureus have been identified in CRS patients but further studies are needed to determine their role in the etiology of the disease, said Dr. Wang. Studies of CRS patients’ immune response to superantigens also need to be done, she said.
A number of other factors may contribute to CRS. For example, allergies to pollen or other types of aspirate may result in CRS, said Dr. Bernstein. Many people with nasal inhalant allergies don’t have CRS, noted Dr. Palmer. However, having allergy may lead to inflammation, he said.
Some patients have an allergy or sensitivity to aspirin, which results in the development of polyps and chronic sinusitis, said Dr. Wang.
I have not seen a single piece of evidence that the biofilm is actually causing the inflammation. – -Jens U. Ponikau, MD
Congenital anatomical abnormalities such as a deviated septum or a concha bullosa, which is an enlargement or ballooning of the nasal turbinate, can contribute to sinus obstruction and predispose patients to developing sinus complications including CRS, said Dr. Bernstein. Viral infection can also be a cause the disease, especially in people with a congenital abnormality that puts them at higher risk, he said.
Osteitis, or inflammation of the bone, can generate bacteria that interfere with the mucosal surface in the paranasal cavities, leading to CNS, said Dr. Bernstein.
Another cause of CNS may be the overuse of antibiotics by general physicians, said Dr. Bernstein. Antibiotics may kill good bacteria, allowing more pathogenic types to grow in the paranasal cavities, he explained.
Genetics may also provide some answers to the etiology of the disease. Dr. Bernstein and his colleagues are collecting buccal swabs from CRS patients with paranasal polyps to determine if a genetic cause exists. We’re working on isolating single nucleotide polymorphisms that are responsible for proinflammatory cytokines, he said. This discovery may help answer why polyps recur in some patients even after they undergo surgery. IL-1 beta at +3945 position may have an altered nucleotide at that position, which may upregulate the synthesis of that proinflammatory cytokine protein, he said.
Post-surgical inflammation, environmental triggers, allergens, and cilia dysfunction often also contribute to the disease, said Dr. Palmer.
Additionally, a patient’s immune system is very sensitive to external triggers, including environmental allergens, climate, and psychological/mental stresses, and may contribute to CRS, noted Dr. Wang.
Inflammation associated with CRS can have many causes; however, end-stage treatment of the disease is usually the same, said Dr. Palmer. Generally, physicians use sinus surgery and a variety of medications to treat CRS.
Functional endoscopic sinus surgery may help get rid of limited CRS, said Dr. Bernstein. However, if the patient has hyperplastic disease with nasal polyps, surgery alone won’t help. You have to remove the chronic disease and provide thorough postoperative care, which includes cleaning and medication, he said.
Helpful agents may include oral or topical steroids and anti-inflammatory drugs, he said, adding that erythromycin is often used as an anti-inflammatory rather than an antibiotic.
Overall, the various causes of CRS make it harder for antibiotics only to cure certain cases, said Dr. Ramada.
If it was only bacterial, people receiving antibiotics would be more readily able to rid themselves of the condition, said Dr. Palmer.
In addition, because biofilms are so large, they may be difficult to eradicate with antibiotics it they are the cause of disease, noted Dr. Bernstein.
Other medications for CRS include leukotriene antagonists, which help block airway constriction and mucus production, and topical diuretics such as amiloride, which block sodium channels and decrease swelling, said Dr. Bernstein.
In general, after patients undergo treatment, they can experience three to five years without a major recurrence, he added.
Dr. Wang noted that treatment for each individual patient with CRS can be tailored to target the etiology of the disease. For instance, some patients need desensitization to fungi, aspirin, or other allergens, she said. Some patients may need oral, intravenous, or topical antibiotics, whereas others need surgery, and many patients need both approaches.
She also finds environmental as well as psychological and mental factors to be important modulators of the immune system that should be addressed. CRS patients are usually counseled to avoid environmental triggers such as mold, mildew, dust, pollens, and smog, if possible. This means maintaining as clean a house as possible, staying indoors on high smog and pollen days, and sometimes even moving to a different location, she said. In addition, stress management and lifestyle modification through healthy diet and exercise are important in maintaining a strong and balanced immune system, she said.
If fungus is a cause of CRS, antifungal therapy may be effective, said Dr. Ponikau. In one open-label pilot study conducted by Dr. Ponikau and his colleagues, amphotericin B (SinuNase, Accentia Biopharmaceuticals) improved symptoms in 75% of 51 patients with CRS. Endoscopically, 18 (35%) became disease-free. CT scans before and after treatment demonstrated a significant reduction in inflammatory mucosal thickening in the paranasal sinuses. Further, in a randomized, placebo-controlled, double-blind, single-center trial of 30 patients, Dr. Ponikau and his colleagues found that intranasal amphotericin B reduced inflammatory mucosal thickening on both CT scan and nasal endoscopy and decreased the levels of intranasal markers for eosinophilic inflammation in patients with CRS.
Based on these data, the drug’s manufacturer is preparing to commence its Phase III double-blinded, placebo-controlled clinical trial with amphotericin B to treat post-surgical patients suffering from recurrent CRS. The FDA has granted fast track status for the approval process. Accentia obtained exclusive worldwide rights to market and sell products based on Mayo Clinic’s patented treatment method using amphotericin B.
Topical amphotericin B nasal spray did not prove to be beneficial in a controlled double-blind study, noted Dr. Bernstein.
Although current therapies are limited, treatment of CRS will change dramatically as researchers continue to better understand the causes of disease, concluded Dr. Palmer.
©2006 The Triological Society