It has long been recognized that allergic rhinitis and sinusitis are commonly associated with asthma. Studies have observed a high coincidence of asthma and sinusitis and have repotted that approximately 50% of patients with asthma have abnormal sinus x-rays. l'6 Despite observations of an association between sinusitis and asthma, a direct cause and effect relationship remains to be established. It has been observed that treatment of sinusitis may improve the course of asthma. However, these observations are anecdotal or from uncontrolled studies. The mechanisms by which upper respiratory nasal or sinus disorders might act as a trigger of asthma remain undefined and poorly understood.
In this review, we explore these questions by reviewing the literature regarding the association of sinusitis and asthma, the microbiology of sinusitis, and the possible mechanisms by which upper respiratory tract disease might exacerbate episodes of asthma. Lastly, we will discuss the clinical studies suggesting that treatment of sinusitis improves the course of asthma, and review the experience at our institution.
SINUS X-RAY ABNORMALITIES AND ASTHMA
The association between sinusitis and asthma was first recognized 60 years ago when Gottleib reported that 26% of 117 adult asthmatics demonstrated abnormal sinus x-rays. ' A prospective study of adult asthmatics admitted to National Jewish Center for Immunology and Respiratory Medicine found 58% to have abnormal sinus x-rays (R. T. Rolfs, R. A. F Clark, K. Kreiss. Unpublished data). Other studies have found that approximately 50% to 70% of adult patients with asthma have abnormalities on sinus x-ray.2"6 We prospectively evaluated 42 consecutive asthmatic children admitted to National Jewish (aged 7 to 17 years) and found 52% had abnormal sinus x-rays.7 This finding is similar to that of Racheleisky and coworkers,8 where 53% of children with respiratory allergy had abnormal sinus x-rays. We retrospectively reviewed the sinus x-rays of asthmatic children 1 to 8 years of age admitted to National Jewish over a 5-year period and found 72 of 98 (73%) with abnormal sinus films. Although sinus x-ray abnormalities are common in patients with asthma, some normals also demonstrate sinus x-ray abnormalities. Abnormal sinus films were demonstrated in 25% of healthy, asymptomatic airmen.9 However, only 16% of these (4% of the total) had significant abnormalities (greater than 5 mm membrane thickening) . A recent study in normal children older than 1 year of age demonstrated that 7% without upper respiratory symptoms had abnormal sinus x-rays.10 Therefore, it appears that asthmatics of all ages often have a higher prevalence of sinus x-ray abnormalities than the healthy population.
MICROBIOLOGY OF SINUS X-RAY ABNORMALITIES
The microbiology of these sinus x-ray abnormalities has only recently been evaluated in patients without respiratory allergy. WaId and associates11 studied the bacteriology of acute sinusitis in children, using direct sinus aspiration. Cultures revealed aerobic bacteria, primarily Streptococcus pneumoniae, Hemophilus influenzae, and BranhameUa catarrhalis. No correlation was found between bacteria identified in the sinuses and nasopharynx. Studies in adult nonatopic populations with acute sinusitis revealed similar organisms. 12· 13 Other studies of direct sinus aspiration of children and adults with chronic sinusitis without asthma demonstrated primarily anaerobic organisms.14·15 In these studies, sinus aspirates that yielded significant bacterial colony growths correlated well with radiographie rinding of maxillary mucosal membrane thickening of 5 to 8 mm or greater.
In patients with sinusitis and asthma, the bacteriology of sinus aspirates has not routinely been studied. Friedman and coworkers16 reported the results of sinus aspirates performed on five asthmatic children with acute sinusitis. Organisms identical to those found in children with acute sinusitis without asthma were cultured. Sporadic reports of sinus aspirates of pediatrie and adult patients with chronic sinusitis and asthma demonstrated H influenzas (usually ß-lactamase producting), Staphylococcus aureus, or anaerobic bacteria.8-17'18 These reports involved patients enrolled in studies for reasons other than the systematic determination of sinus cultures and represent selected cases refractory to treatment.
Two studies have systematically examined the microbiology of chronic sinusitis in asthmatic patients. In a study of 2 1 adult patients with asthma and abnormal sinus radiographs, Berman and colleagues4 reported that five of 25 sinuses (20%) demonstrated positive cultures as determined by direct sinus aspirate. Organisms obtained were othemolytic streptococci, diphtheroids, and H influenzae. In a recent study at our institution, 42 children with asthma and abnormal sinus radiographs were cultured by direct aspiration of the most involved maxillary sinus.19 Only four of the patients (10%) demonstrated positive cultures. S pneumonias, H influenzae, S aureus, and an anaerobic streptococcal species were identified. AU positive cultures were associated with maxillary sinus mucous membrane thickening of 5 mm or greater. Therefore, when systematically examined, it appears that in asthmatic children and adults with chronic sinusitis, it is rare for aspirates of maxillary sinuses to yield bacterial growth.
If the sinus radiographie abnormalities do not represent bacterial infection, what are the other possible etiologies? Viral infection of the sinuses has occasionally been documented in the atopic and nonatopic population. There are scattered reports of isolation of rhinovirus, adenovirus, and influenza A.20 In the 12 patients in our series whose sinus aspirates were cultured for viruses, only one culture revealed a rhinovirus.7 Therefore, it does not appear that viral infection plays a prominent role in the abnormal sinus radiographs seen in patients with sinusitis.
Histologie findings of abnormal sinus membrane tissue obtained from asthmatic patients appear similar to that of the bronchial mucosa. 21·22 The mucous membranes are edematous with cellular infiltrations of plasma cells, lymphocytes, eosinophils, and polymorphonuclear leukocytes. Basement membrane thickening with hyperplasia of epithelial goblet cells may also be seen. In more advanced disease, destruction of the epithelial surface with accumulation of eosinophils, Curschmann's spirals, and Charcot-Leyden crystals may be observed. A recent study has demonstrated eosinophil-derived major basic protein within the sinus mucous membrane. 23 Therefore, given the general absence of bacterial or viral contamination of sinuses in patients with asthma, and the histologie similarities to asthma, we suggest that the abnormal sinus radiographs seen in these patients do not indicate primary infection, but rather represent the noninfectious inflammatory changes characteristic of asthma and respiratory allergy. If this is correct, one might further speculate that asthma represents a state of hyperresponsiveness and inflammation characteristic of the entire respiratory tract and is not limited to the bronchial mucosa and smooth muscle.
In 1925, Gottlieb reported his experience with 117 cases of asthma, of which 3 1 had significant disease of the sinuses.1 Based on then-current concepts, he postulated four mechanisms that might explain how sinus disease could precipitate or worsen asthma (Table 1). It is astonishing that in the intervening 60 years our understanding of this relationship and the mechanisms involved has not progressed substantially.
Concepts of mechanisms that might explain how sinus disease and asthma are linked have been recently reviewed.24 A current list of sinusitis mechanisms that may worsen asthma is not very different from that of Gottlieb, but incorporates recent knowledge about the pathogenesis of asthma, inflammation, and hyperactivity (Table 2). Strict separation of these mechanisms is unlikely, because several may be operative at the same time.
Mechanisms Postulated by Gottlfeb (1925 J Linking Nasal Disease to Asthma
A Modern List of Potential Mechanisms Unking Upper Respiratory Tract Disease with Asthma
Patients with chronic sinusitis often complain of significant posterior nasal drainage.8 It is likely that these secretions are a contributing factor that precipitate episodes of asthma. Studies from the 1920s and 1930s demonstrated that material placed into the upper respiratory tract and sinuses can be recovered from the tracheobronchial tree.25"27 More recently, Huxley and coworkers28 reported that when small amounts of indium chloride were placed into the nasal vault, aspiration into the tracheobronchial tree was demonstrated in 50% of normal sleeping subjects. Ormerod29 instilled iodized poppy seed oil into the lower airways for bronchography, which could later be recovered from both the nasal and sinus passages, suggesting a bidirectionality of secretion transport. These studies suggest that a sizeable portion of the normal population may aspirate nasal secretions while sleeping, but this is not likely to cause symptoms or disease, and secretions must be effectively cleared from the bronchi. When postnasal drip occurs in the context of hyperreactive airways, it is possible that this aspirated material may aggravate the underlying inflammatory state, thus worsening the pre-existing asthma. The inflammatory processes in both the lower and upper airways might influence the function and pathogenesis in the other.
Aside from their mechanical direct effect, secretions dripping into the pharynx might also alter lower airway tone through neural reflexes (see Nasobronchial Reflexes). Investigators have been able to demonstrate in animals and humans that irritation of either the nasal mucous membranes or pharynx can cause bronchospasm in the lower airways. Thus, secretions from the upper airways might worsen asthma by direct aspiration into the lower airways or may increase bronchial tone by a neural reflex.
Reabsorption of Mediators or Chemotactic Bactors
Gottlieb postulated that reabsorption of a "protein material" from the involved areas of the sinuses was an important mechanism that produced asthma. He observed a temporal improvement of asthmatic symptoms that occurred following sinus drainage or removal of diseased sinus tissue.1 Since that time, a number of studies have reported that surgical treatment of sinus disease in patients with asthma may improve the course of asthma in some individuals. I7'30'3^ The improvement of asthma following surgery suggests that removal of inflamed sinus tissue may remove a source of inflammatory mediators which might be acting to precipitate episodes of asthma or aggravate ongoing bronchial hyperreactivity. Surgery of the sinuses would remove resident cell types (endothelium and epithelium) that are capable of producing mediators, as well as the inflammatory cells (neutrophils, eosinophils, lymphocytes) and chemotactic factors. Lastly, some types of surgery might remove irritant and other neural receptors, which could initiate nasobronchial reflexes (see below). Because all these sources of signals to the lower airways are potentially involved, the efficiency of surgical removal of nasal and sinus mucosal tissue is perhaps not surprising.
If reabsorption of elaborated mediators or chemotactic factors is an important mechanism to subsequent lower airways dysfunction, then the site of the inflammation may not have to be limited to the upper respiratory tract. Whether distal sites of inflammation alter airway function is unknown, although it has been observed that patients with arthritic complaints frequently have airways disease, but whether their airways are hyperresponsive has not been determined.35 Recent studies demonstrate that in asthmatics, chemotactic factors increase in the blood following exercise,36 therefore, it is possible that blood-borne factors may affect tissues supplied by the bronchial and pulmonary circulation.
Breathing Cold, Dry Air
Gottlieb postulated that "the effect of cold, dry air combined with the presence of infected material" could worsen existing asthma.1 Interestingly, he correctly identified a factor also implicated as a mechanism of exercise- induced bronchospasm. Subsequent studies suggested that nasal obstruction probably alters lower airways function. Togawa and Ogura37 assessed pulmonary mechanics in which decrements correlated well with the severity of nasal disease. Pulmonary function has also been shown to improve following surgical relief of nasal obstruction.38 Wyllie and associates39 reported increased pulmonary resistance after packing the nose with petrolatum for 96 hours. Interestingly, these subjects had many other physical complaints related to the nasal obstruction including fatigue, sleeplessness, and dyspnea. Recently, in six of 12 patients with allergic rhinitis and asthma, Van and Salome40 observed a significant decrease in FEV1 (forced expiratory volume at one second) when the nose was obstructed following nasal challenge with histamine. Although all of these means of effecting nasal obstruction lead to increased mouth breathing of relatively cold and dry air, the results could also be explained by activation of neural reflexes.
As originally suggested by Sluder in 1919, 4t it is likely that nasobronchial reflexes are involved in the association between upper respiratory tract disease and asthma. A nasobronchial reflex has been demonstrated in animal and human models by nasal presentation of silica particles,42 sulfur dioxide,43 electrical stimulation,44 cold air,45 mechanical irritation,46 or fumes,44·47·48 which is usually blocked by either anticholinergics45·47·48 or by resection of the neural connections between the nose and lungs.46·47·49·50 Holtzman and coworkers51 have demonstrated that increased airways responsiveness in allergic rhinitis patients could be attenuated by ganglionic blockade, suggesting that autonomie reflexes are important. In animals, Bunckner and colleagues52 have elegantly demonstrated that a viral infection of the nose was associated with lower airways dysfunction due solely to activation of nasobronchial reflexes. The presence of a nasobronchial reflex has not always been demonstrated, causing some to question its importance.53 Nevertheless, a great body of evidence strongly suggests that a nasobronchial reflex exists and can result in increased lower airways resistance.
The presence of a nasobronchial reflex as a trigger for asthma in patients with sinusitis has not been studied. However, we believe it is likely that inflamed nasal or sinus tissue or pharyngeal irritation from posterior nasal drainage is an important mechanism that links upper and lower respiratory tract disease.
Diminished ß-Adrenergic Responsiveness
Although this is probably the most speculative of the proposed mechanisms, upper respiratory tract infections and asthma have been associated with decreased ß-adrenergic function of granulocytes. 53 However, little is known about ß-adrenergic function of the airways smooth muscle in asthmatics who have sinusitis or rhinitis. It seems clear that upper respiratory tract disease is linked to asthma. Whether upper respiratory tract disease is a cause of asthma or simply a manifestation of a common underlying process is not known. The potential mechanisms are numerous, and interaction between these are likely.
Surgical treatment of sinusitis in asthmatic patients with sinus radiographie abnormalities is more empiric than determined by prospective clinical studies. In 1936, Weille4 studied 500 asthmatic patients with abnormal sinus radiographs. Patients were treated either with or without sinus surgery. No beneficial effect of sinus surgery was found; in both groups, approximately two thirds were "cured or better" and one third worse. Weille concluded that "mucous membrane instability is seen throughout the respiratory tract in many asthmatic patients. Such instability . ... is part of asthma; in the nose it is part of the same underlying condition."
Interest in the relationship between sinusitis and asthma subsequently waned. It was not until Davison,30 in 1969, reported that 24 of 50 patients (50%) with asthma treated surgically for sinusitis had improvement of their chest symptoms. Subsequent to this study, numerous other case reports have appeared in the medical literature that attempt to test the efficacy of sinus surgery in patients with asthma.17·30'34 It is of interest that Weille's report in 1936 more closely approaches a controlled clinical study than recent reports. The difficulties in performing controlled studies will most likely not allow workers to determine whether this form of therapy is useful. Nevertheless, it is the clinical observation that many steroid'dependent asthmatic patients with sinusitis often improve following sinus surgery.
In patients with both acute32 and chronic14 sinusitis but without asthma, improvement in symptoms and radiographie abnormalities in those treated with antibiotics seemed to relate to the in vitro sensitivity of the organisms obtained from the sinus. In patiente with asthma, the effect of treatment of sinusitis (in terms of resolution of the sinus radiographs) is less clear. Businco and coworkers54 treated 55 asthmatic children with abnormal sinus radiographs. Seven of 13 patients (54%) treated with antibiotics had improvement in their sinus radiographs, whereas 28 of 42 patients (67%) improved on intranasal steroids. In our evaluation of 42 asthmatic children with abnormal sinus radiographs, patients were randomized to receive 3 weeks of antibiotics (ampicillin), intranasal steroids, intranasal decongestants, and oral decongestants, or identical placebos. Although nine of 21 patients (43%) had radiographie improvement on active medication, eight of 21 patients (38%) improved on placebos. Therefore, it appears that in the asthmatic population with abnormal sinus radiographs, radiographie abnormalities may improve without antibiotics or spontaneously.
Improvement of asthma with pharmacologie treatment of sinusitis has also been studied. Friedman and colleagues16 evaluated and treated five children with acute sinusitis associated with exacerbations of asthma. Treatment of their sinusitis and asthma resulted in improvement of both disorders. Rachelefsky and coworkers18 found that 80% of 48 asthmatic children treated for sinusitis were able to discontinue bronchodilators after treatment with antibiotics. In a study conducted at our institution, 42 asthmatic children with moderate to severe asthma and abnormal sinus radiographs were selected for study.19 Patients were randomized in a doubleblind fashion to receive either 3 weeks of ampicillin, oral decongestants, intranasal steroids, and nasal decongestants, or identical placebos. Patients were monitored with daily asthma symptom scores, twice daily spirometrie measurements, the need for additional bronchodilators and steroids, and methacholine reactivity before and after the 3-week study. Patients were all cultured for bacteria by direct sinus aspirate, as previously discussed. Patients were «evaluated at the end of 3 weeks for improvement in sinus radiographs. Most patients in both the activeand control-treated groups showed no change in the radiographs; however, an equal number of demonstrated improvement, as discussed previously. Despite the lack of bacterial contamination within the sinuses and the equal rate of improvement in the sinus radiographs, it was clearly demonstrated that those patients who received active medication for the sinusitis had significantly improved asthma symptom scores. Additionally, patients who received active medications required significantly less bronchodilators and steroids. Methacholine challenges performed before and after treatment showed a trend toward improvement in reactivity in those treated with active medications. A similar trend occurred in daily pulmonary function. Therefore, in our controlled study as well as other noncontrolled studies,16·18 treatment of sinusitis appears to improve the course of asthma.
The recommendations to be discussed for the treatment of sinusitis in asthmatic patients are based on our understanding of the pathogenic processes that lead to sinusitis, the mechanisms in which sinusitis might worsen asthmatic symptoms, the clinical studies performed, and our clinical experience. We evaluate all patients with asthma who have symptoms suggestive of sinusitis for radiographie evidence of sinusitis, and all patients with poorly controlled or steroid-dependent asthma. Fiberoptic study of the upper airways often allows more sensitive detection of secretions within the posterior nasal vault or nasopharynx. Those with 5 mm or greater of maxillary sinus membrane thickening, opacification, or air-fluid level are treated.
We base our medical treatment on the assumption that nasal mucous membrane inflammation has occurred, obstructing the sinus ostea, preventing normal sinus drainage and producing sinus congestion and possibly bacterial infection. Nasal washes with saline immediately prior to topical administration of corticosteroide (beclomethasone or flunisolide) remove irritants, allergens, and mucus, and reduces the inflammatory response. Topical nasal decongestants may be prescribed for the first 3 to 5 days of therapy, if nasal obstruction is severe. Oral antihistamines and decongestants may also be used. Additionally, amoxiciltin (or trimethoprim/ suliamethoxazole in penicillin-sensitive patients) is given for at least 3 weeks.
Patients with severe rhinopharyngitis are treated similarly but without antibiotics. If no improvement in nasal symptoms occurs after 6 to 8 weeks of therapy and the asthma remains poorly controlled, we recommend a sinus aspiration and therapeutic lavage of the involved maxillary sinus(es). The aspirated material should be stained for bacteria and fungi and cultured for aerobic and anaerobic bacteria and fungi. Antimicrobial therapy should be adjusted accordingly.
We select patients for more invasive surgical procedures of the sinuses if the sinus disease continues uncontrolled and the asthmatic symptoms are extremely labile or dependent on unacceptable doses of oral corticosteroids. The difficult decision to pursue aggressive sinus surgery is made on an individual basis with the knowledge that many patients may not enjoy improvement of their asthmatic symptoms. Nevertheless, it is our experience that surgical removal of diseased sinus tissue often improves the course of asthma.
The evidence that upper airway disease worsens asthma is circumstantial. Nevertheless, there is the consistent observation in many patients that control of asthma remains difficult when their sinus disease is not treated. Treatment of nasal or sinus disease often results in improvement of asthma in these patients. Many potential mechanisms may be involved, but two are most likely to be important: posterior nasal drainage and activation of nasobronchial reflexes. Regardless of the mechanisms, the upper and lower respiratory airways seem to share the same physiologic features of inflammation and hyperresponsiveness. Haseltine stated in 1925: "he [the patient] cannot have bronchospasm with a previously entirely normal nose."55 If this statement is true, and it probably is, then the mechanisms by which sinusitis worsens asthma need to be carefully investigated.
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Mechanisms Postulated by Gottlfeb (1925 J Linking Nasal Disease to Asthma
A Modern List of Potential Mechanisms Unking Upper Respiratory Tract Disease with Asthma