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Rhino-Sinusitis: Clinical Pearls

Unified Airway Hypothesis: Truth or Fiction

“There’s a lot of data about associations between the upper airway and the lower airway and there is no doubt, absolutely no doubt whatsoever, that
the upper airway influences the lower airway,” said Michael Kaliner, MD, Medical Director of the Institute for Asthma and Allergy in Wheaton and Chevy Chase, MD. Whether or not they are one unified airway system, however, is unclear. Some of the epidemiologic, physiologic, and therapeutic evidence examining the association between the lower and upper airways was presented by Dr. Kaliner.

Epidemiology
Several demographic studies indicate a strong correlation between upper and lower airway conditions. For example, 75% to 95% of asthma patients have rhinitis and approximately 25% of rhinitis patients have asthma. Furthermore, about two-thirds of patients with severe asthma also have sinusitis. In asthmatic children, 53% to 75% have abnormal sinus x-rays (Ann Allergy Asthma Immunol 1996;77:6-15, J Allergy Clin Immunol 1997;99:S138). Finally, in a 23-year follow-up study, 10.5% of subjects with allergic rhinitis developed asthma compared to only 3.6% of non- allergic subjects (Allergy Proc 1994; 15:21-25).

Physiology
Several physiologic mechanisms involve both upper and lower airways. One example is the naso-pulmonary reflex. To illustrate this reflex, Dr. Katiner discussed a study performed 30 years ago in which silica particles into the nose increased lower airway resistance and decreased lung volume. This reflex was dependent on the trigeminal nerve (Am Rev Respir Dis 1970;101;768-769). Another example to illustrate the connection between the two systems can be observed in exercise- induced asthma which worsens with mouth breathing (Am Rev Respir Dos 1976;118:65-73).

In patients with asthma and allergic rhinitis, studies have shown that nasal administration of histamine or allergens can significantly affect bronchial functions (Eur J Respir Dis 1983;64:105-106, J Allergy Clin Immunol 1992;89:611-618), further supporting the hypothesis that the two airways have strong physiological connections.

Treatment
Some of the most compelling data showing a connection between the upper and lower airways is found in clinical trials. For example, intranasal glucocorticoids (beclomethasone) improves both rhinitis and asthma symptoms (J Allergy Clin Immunol 1993;91:97-101). Similarly, antihistamines which are used to treat rhinitis improve pulmonary function (J Allergy Clin Immunol 1997;1000:781-788) and asthma symptoms (J Allergy Clin Immunol 2001;104:751-762).

Another interesting set of data comes from patients with sinusitis and asthma. Currently, 25% to 70% of asthmatic adults and 20% to 60% of asthmatic children have sinusitis. Studies have shown that medical or surgical treatment of sinusitis can improve asthma. For example, earlier reports of sinus surgery (pre -1988) showed 22% to 85% of patients had improved asthma symptoms. Using FESS (functional endoscopic sinus surgery) to treat sinusitis has generally improved asthma scores. In addition to the clinical data, Dr. Kaliner said, “our own clinical data, which is certainly anecdotal, clearly suggest that good medical management of sinusitis makes asthma much easier to treat.”

Dr. Kaliner also said that certain medications for asthma (inhaled corticosteroids, immunotherapy) may also improve rhinitis while certain medications for rhinitis (anithistamines, nasal corticosteroids, immunotherapy) may improve asthma symptoms. The use of b-agonists or theophylline for asthma do not improve rhinitis and Dr. Kaliner said treatment with leuokotriene antagonists requires further studies before any conclusions can be made.

Concluding Remarks
Dr. Kaliner ended his presentation by saying that there are numerous studies linking the upper and lower airways but there are differences and “don’t think you can make the conclusion that if a drug works here, it’s going to work there, because it doesn’t,” adding, “on the other hand, there’s no question that we need to treat the upper airway and the sinuses in order to effectively treat the lower airway.”

Nasal Polyps in Noninfectious Inflammation of the Upper Airway

“I don’t need to tell this audience how important nasal polyps are if only from their prevalence (4% of populations) — not to mention the morbidity that occurs from them,” said Mark Dykewicz, MD, Professor of Internal Medicine and the Director of the Training Program for Allergy and Immunology at St. Louis University in St Louis, MO. Nasal polyps are often associated with a number of disorders including aspirin intolerance, aspirin tetrad syndrome (aspirin intolerance, nasal polyps, sinusitis, and asthma), non-allergic asthma, chronic sinusitis, allergic fungal sinusitis. cystic fibrosis, Churg-Strauss syndrome, Young syndrome, and Kartagener syndrome.

Nasal polyps are translucent, typically pale gray, and are often bilateral, multiple, movable, and arise from the middle meatus. Histological examination of polyps shows that most are associated with eosinophilic inflammation, but neutrophils predominate in polyps from cystic fibrosis patients. Typically they have pseudostratified ciliated columnar epithelium, thickened epithelial basement membranes, and a high stromal eosinophil count. They are a mixture of lymphocytes, plasma cells, and eosino-phils with few glands and essentially no nerve endings.

The pathophysiology of nasal polyps is not completely understood and is probably multifactorial. Mediators in nasal polyps include histamine, serotonin, leukotrienes (LTB4, LTC4, LTD4, LTE4), IL-5, norepinephrine, kinins, TAME-esterase, and possibly prosta-glandin D2. “If we look at potential areas for intervention, we do know that histamine can be released as part of nasal polyp process and there is some data which would suggest that histamine levels may even be higher in nasal polyps than in turbinates,” said Dr. Dykewicz. Another important mediator may be IL-5 from eosinophils (J Allergy Clin Immunol 1997;99:837-842), present in nasal polyps from both allergic and nonallergic patients. Recently, staph superantigens have also been implicated in the development of nasal polyps in as many as half of nasal polyp patients. A study by Bachert et al (J Allergy Clin Immunol 2001;107:607-614) indicates that specific IgE to staph enterotoxins A and B may initiate a cascade of effects that act upon multiple cell types to promote the development of nasal polyps.

Treatment
Topical corticosteroids alone often control symptoms and prevent nasal polyp recurrence after surgical removal (JAMA 1997;278:1849-1854, J Allergy Clin Immunol 1998;102:S117-S144, Arch Otolaryngol Head Neck Surg 1997;123: 595-600). However, systemic corticosteroids should be attempted prior to surgical polypectomy. In a study by Blomqvist et al (J Allegy Clin Immunol 2001;107:224-228) comparing medical treatment versus medical treatment plus surgery, it was found that in most cases, medical treatment was sufficient. Surgery is only beneficial if nasal obstruction is the main problem after steroid treatment.

Chronic Sinusitis
There are four major pathophysiologic processes for chronic sinusitis:
• Chronic infectious sinusitis
• Chronic inflammatory sinusitis
• Chronic hyperplastic eosinophilic sinusitis
• Allergic fungal sinusitis

In chronic inflammatory sinusitis, there is no tissue eosinophilia and it believed that this syndrome results from chronic or recurrent occlusion of the sinus ostia due to allergic or nonallergic rhinitis, or anatomic problems. Chronic inflammatory sinusitis is generally responsive to surgical interventions. In contrast, chronic hyperplastic eosinophilic sinusitis does not respond well to surgery. Chronic hyperplastic eosinophilic sinusitis is frequently associated with not only nasal polyps, but also asthma, atopy, or aspirin sensitivity. It has a strong inflammatory, but non-infectious process. “A majority of patients that we’re seeing with chronic sinusitis might have this,” stated Dr. Dykewicz.

Unfortunately, there are not many controlled studies involving treatment of non-infectious chronic sinusitis syndromes. Since Dr. Meltzer discussed treatment of chronic sinusitis using nasal steroids, Dr. Dykewicz reviewed other interventions. For example, in patients with aspirin sensitivity, rhino-sinusitis and asthma, Dr. Donald Stevenson’s group at the Scripps Clinic has shown that aspirin desensitization can decrease the number of sinus and polyp operations per year. In regard to antileuko-triene as a treatment option for chronic hypertrophic eosinophilic sinusitis, very few controlled studies have been performed (Am J Respir Care Med 1998; 157:1187-1194, Ear Nose Throat J 2000;79:18-20,24-25) and Dr. Dykewicz said further studies are needed.

Another possible treatment option for non-bacterial, chronic hypertrophic eosinophilic sinusitis may be macrolides based on their potential anti-inflammatory actions on the sinus mucosa (Advances in Therapy 2001; 18:75) but Dr. Dykewicz cautioned that controlled studies to assess their potential benefit are needed.

Nonallergic Rhinitis Syndromes
Nonallergic rhinitis represents a heterogenous group of disorders and one recent survey estimated that 25% of patients presenting at allergists’ offices had nonallergic rhinitis (Ann Allergy, Asthma, & Immunol 2001;86:494).

Treatment of nonallergic rhinitis syndromes are often broad- based therapies such as nasal steroids, nasal azelastine, or treatment for relief of specific symptoms (i.e., oral decongesants). Unfortunately, nonallergic rhinitis is generally less responsive to therapy than allergic rhinitis but one recent study by Webb et al (Ann Allergy, Asthma, & Immunol 2002;88:385-390) showed fluticasone to be effective in nonallergic rhinitis even when nasal eosinophils were absent. Also, the antihistamine azelastine has had some beneficial effects in vasomotor rhinitis patients possibly due to its known anti-inflammatory properties (Ann Allergy Asthma, & Immunol 2001; 86:28-35).

Concluding Remarks
We know that patients with polyps and chronic sinusitis tend to be more refractory to treatment than those with allergic inflammation and that is the
conundrum. At present, if nasal steroids fail to treat these patients, there is no algorithm available based on controlled studies to determine the next treatment option, and further studies are needed.

The Role for Nasal Corticosteroids in Rhinosinusitis

Eli Meltzer, MD, Clinical Professor of Pediatrics at the University of San Diego, San Diego, CA, began his presentation by asking how many clinicians in the audience prescribe intranasal corticosteroids for treatment of sinusitis. Most of the audience raised their hands. When Dr. Meltzer then asked who could quote studies that are the basis for this treatment regimen, only a few doctors raised their hands. The reality is that there are very few clinical trials on this subject but Dr. Meltzer provided the audience with a review of the principles of managing sinusitis and the clinical evidence for the use of intranasal corticosteroids as a treatment option.

The principles of management of sinusitis are:
• Educate the patients
• Reduce predisposing factors
• Treat the infection
• Improve nasal/sinus ostial patency
• Supress mucosal inflammation
• Prevent reinfection
• Restore well-being

Most of these principles are best achieved with intranasal corticosteroids (Table 1) and Dr. Meltzer provided the audience with the available evidence to support the use of top-ical cortico-steroids for the treatment of acute, recurrent, and chronic sinusitis.

Acute Sinusitis
In acute sinusitis, studies have shown both budesonide (Ann Allergy Asthma Immunol 1997;78:598) and flunisolide (J Allergy Clin Immunol 1993;92:812) improve sinusitis symptoms. In a recent study by Meltzer et al (J Allergy Clin Immunol 2000;105:S200) fluticosone propionate was compared to placebo in patients with at least 2 moderate or severe sinusitis episodes in 6 months (or 3 in 12 months) (Note that patients were also given the antibiotic cefuroxime for first 20 days). Throughout the 7-week study, the fluticosone-treated patients showed improvements and “individual symptoms of mucopurulent drainage, nasal congestion, facial pain, sinus headache, and cough were better in the intranasal corticosteroid group compared to placebo,” said Dr. Meltzer. In a recent study by Dolor et al (JAMA 2001;286: 3097-3105), “clinical success” was reported in 93.5% of sinusitis patients given fluticasone + cefuroxime compared to only 73.9% in patients given placebo + cefuroxime.

In the largest study performed, 407 sinusitis patients were given mometasone (n = 200) or placebo (n = 207) as adjunct therapy to antibiotic treatment (Augmentin) and over the course of the 3- week study, symptoms of congestion, facial pain, headache, nasal drainage, rhinorrhea, and cough were improved in the mometasone-treated group compared to placebo (J Allergy Clin Immunol 2000;106:630-637). Furthermore, relief from symptoms was quicker in the mometasone group and was independent of whether the patients had an underlying allergic or nonallergic profile. Examination of CT scans in this study revealed improvements in the mometsone group but Dr. Meltzer warned, “the percent of patients who had improved CT was not 100%,” adding, “the inflammation does not immediately resolve, although it does improve.” It often takes a long time for CTs to become
normal.

Summarizing the studies, Dr. Meltzer said that acute sinusitis is an expensive and troublesome condition. Adjuntive therapy with intranasal corticosteroids appears to provide additional benefits compared to antibiotic therapy alone since both inflammation and infection need to be addressed in acute sinusitis.

Recurrent Sinusitis
In a continuation of an acute sinusitis study involving fluticasone (J Allergy Clin Immunol 2000;105:S200), treatment for an additional 6 months was performed and it was found that “the number of patients who had at least one recurrence was less in those who continued on the intranasal corticosteroid (25%) compared to those who had only an intranasal placebo spray (39%)” (J Allergy Clin Immunol 2002;109:S86).

In a study presented at the annual AAAAI meeting last year, Drs. Van Cauwenberge and Norcross found significantly fewer recurrences of sinusitis and significantly longer time to first recurrence in patients given fluticasone compared to placebo.

Summarizing the recurrent sinusitis studies, Dr. Meltzer said that fewer patients develop a recurrence of acute sinusitis when maintained on usual doses of intranasal corticosteroids. Further-more, patients maintained on an intranasal corticosteroid delay the potential of a recurrence compared to maintenance therapy with a placebo.

Chronic Sinusitis
As discussed earlier by Dr. Dykewicz, chronic sinusitis can have many contributing factors including infection and/or noninfectious inflammation. In a study by Subramaniam et al (J Allergy Clin Immunol 1999;103:S249), 19 patients with chronic sinusitis were given intranasal corticosteroids plus oral prednisone. Of 19 patients, 17 showed improvements in symptoms and CT scores.

In another study, 200 patients with chronic sinusitis were given antibiotics (4 weeks), topical decongestants (2 weeks), and intranasal corticosteroids. It was found that after 1 month of treatment, symptoms improved in all patients (Allergy Asthma Proc 1997;18:169-175). In a 2-year follow-up of the patients, only 6% required surgery.

Concluding Remarks
Dr. Meltzer ended his presentation by acknowledging that while many clinicians do use intranasal corticosteroids in the treatment of sinusitis and it appears that these agents are beneficial, more studies are needed. “We need to generate more data and develop more studies to better clarify the value of intranasal corticosteroids in medical care,” concluded Dr. Meltzer.


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