Abstract
Upper airway disease, including chronic rhinitis and rhinosinusitis, affect most children with asthma. Over the past two decades, our understanding of the connection between the nose, paranasal sinuses, and lungs has evolved significantly. A growing body of population-based studies has established that allergic rhinitis in children acts as a critical independent risk factor for the development of asthma and that specific allergen immunotherapy has been shown to reduce the risk for developing asthma by approximately 50%. A number of physiologic mechanisms underlie the apparent connection between the upper and lower airways, particularly the systemic spread of inflammation from the nose and sinuses to the lungs. A large number of studies have examined the effect of nasal and sinus therapy, including both medical and surgical treatments, on subjective and objective parameters of asthma. While there is a paucity of randomized, blinded studies, the existing data do suggest that treatment of rhinitis and sinusitis have a beneficial effect on asthma symptoms, pulmonary function, and bronchial hyperresponsiveness.
Keywords
allergy, rhinitis, sinusitis, corticosteroids, antihistamines, surgery, pediatrics
During the past century, practicing clinicians have frequently observed that allergic rhinitis, sinusitis, and asthma coexist in the same patients. Despite a wealth of data supporting an association between the upper and lower airways, not until recently have reliable data emerged that suggest that upper airway disease is a risk factor for the development of asthma and that experimentally induced nasal dysfunction causes asthma to worsen. In addition, there is a growing body of literature demonstrating that appropriate treatment of nasal allergy and chronic sinus disease results in improvements in asthma symptoms and lower airway function. In this chapter, data from a variety of epidemiologic, clinical, and laboratory studies will be highlighted to help clarify our understanding of these complex and important relationships.
Allergic Rhinitis and Asthma
The Epidemiologic Relationship Between Allergic Rhinitis and Asthma
The first population-based studies that explored the relationship between allergic rhinitis and asthma were cross-sectional surveys, which demonstrated that rhinitis and asthma commonly occur together. Many of these studies reported that nasal symptoms occur in 28%–78% of patients with asthma as compared with approximately 5%–20% of the general population. Generally, these data were drawn from a variety of epidemiologic studies and clinical settings in which patients were not interviewed in a standardized fashion and insensitive instruments were used for detecting rhinitis. In a study that utilized a standardized and detailed questionnaire in 478 patients across all age groups, rhinitis was found to be a nearly universal phenomenon in patients with allergic asthma, occurring in 99% of adults and 93% of adolescents. Conversely, asthma has been shown to affect up to 38% of patients with allergic rhinitis, which is substantially higher than the 11.9% global prevalence noted in unselected children.
While these studies demonstrate that rhinitis and asthma frequently occur in the same patients, longitudinal studies are required to accurately assess the actual risk for developing asthma in patients with rhinitis alone.
Settipane and colleagues published the first prospective study regarding the relationship between allergic rhinitis and the development of asthma. In a study that spanned 23 years from entry to completion, 690 adolescents who had allergic rhinitis (without chest symptoms) developed asthma 3 times more often (10.5%) than individuals without rhinitis (3.6%). In another prospective study, Burgess and coworkers enrolled 8583 children, beginning at 7 years of age, and evaluated them at 13 and 43 years of age. Children diagnosed with allergic rhinitis at the beginning of the study had a twofold to sevenfold increased risk of developing asthma at both 13 and 43 years of age. In the most recent study, Rochat and colleagues followed 1314 healthy children from birth to 13 years of age. Allergic rhinitis present at 5 years of age was found to be a significant predictor for developing wheezing between 5 and 13 years of age, with an adjusted relative risk of 3.82. These longitudinal studies, taken together, strongly support the role of allergic rhinitis in childhood or adolescence as a risk factor for developing subsequent asthma.
In children younger than 2 years of age, it has been more difficult to prospectively assess the progression of allergic rhinitis to asthma, in part due to the high prevalence of viral upper respiratory tract infections in this age group. In the study by Rochat, children with allergic rhinitis diagnosed by 2 years of age were not at increased risk of developing wheezing between 5 and 13 years of age. The authors noted that rhinitis at 2 years of age is usually not a persistent condition and will often remit as the child grows older.
Studies dating back over 20 years have demonstrated that adults and adolescents with allergic rhinitis are more likely to have increased bronchial hyperresponsiveness (BHR) than children without rhinitis. More recently, airway hyperresponsiveness has also been shown to be increased in children who have allergic rhinitis but no asthma. Choi and colleagues. performed bronchial methacholine challenges in a group of 115 nonasthmatic children, 4–6 years of age. BHR, assessed as a methacholine dose required to produce wheezing or oxygen desaturation of <8 mg/mL, was significantly more common in children with allergic rhinitis compared with nonrhinitis children (32.5% vs. 9.4%, respectively). Among children with allergic rhinitis, serum total IgE, the number and pattern of skin-prick test responses, blood eosinophil markers, and parental history of allergic rhinitis and atopic dermatitis were not different between the BHR-positive and BHR-negative groups, whereas the persistent type of rhinitis and parental history of asthma were more frequent in the BHR-positive group than in the BHR-negative group.
While nonspecific BHR appears to be more common in children with allergic rhinitis, a second and equally important question is whether this characteristic predisposes them to the development of asthma. A 12-year follow-up study of 291 randomly selected children and adolescents (7–17 years of age) examined a number of historical and laboratory features, including bronchial responsiveness to inhaled histamine. Increased airway responsiveness to histamine was a powerful independent predictor of future lower airway disease, with an approximate fourfold increased risk of developing symptomatic asthma during this period of observation. In a second study, Ferdousi and colleagues followed up a much smaller group of children ( n = 28) for only 2 years. Sixteen of the 28 children were found to have an increase in BHR (assessed by isocapnic hyperventilation of cold air or inhaled methacholine challenge), and 8 of these 16 developed asthma after 2 years.
These studies support the theory that bronchial hyperreactivity may represent an intermediate phase between nasal allergy and symptomatic asthma and may help identify children and adolescents at highest risk for developing asthma.
Pharmaco-economic studies from the past decade have attempted to correlate the presence of rhinitis with asthma severity and health care costs attributable to asthma. In an analysis of a database of 1261 children with asthma, Huse and colleagues compared patients with significant nasal allergy with those who had mild or no symptoms of nasal disease. These investigators noted that patients with more severe rhinitis were much more likely to have nocturnal awakening caused by asthma (19.6% vs. 11.8%, respectively), “moderate to severe asthma” as defined by the National Asthma Education Program (60.2% vs. 51.2%, respectively), or work loss related to asthma (24.1% vs. 21.1%, respectively). Similarly, Halpern and coworkers observed that patients with symptomatic rhinitis used more asthma medications, particularly more inhaled and supplemental oral corticosteroids. Judging from these recent investigations, one can postulate that allergic rhinitis may also be related to increased asthma severity and the use of more potent antiasthma medications. Although these data suggest that rhinitis may be contributing to asthma, an alternative explanation for this association may be that nasal inflammation is a marker for increasing dysfunction of the entire respiratory tract. The possibility of a cause-and-effect relationship is better addressed by therapeutic studies of rhinitis therapy in patients with asthma.
It has been speculated that allergic rhinitis may add a significant burden of disease to patients with asthma. A survey of approximately 800 parents of children with asthma attempted to determine the impact of nasal disease upon their quality of life. In three-quarters of children, rhinitis symptoms preceded the diagnosis of asthma. The concomitant presence of nasal allergy and asthma disrupted the ability to get a good night’s sleep (79%), to participate in leisure and sports activities (75%), to concentrate at work or school (73%), and to enjoy social activities (51%). Importantly, parents (79%) reported worsening asthma symptoms when nasal symptoms were most active, and many (56%) avoided the outdoors during the allergy season because of worsening asthma symptoms. The majority of the parents (60%) indicated difficulty in effectively treating both conditions, and 72% were concerned about using excessive medication. Information collected from this study and other similar data indicate that allergic rhinitis does impose a significant additional symptomatic burden on patients with asthma.
Common Immunopathology of Allergic Rhinitis and Asthma
During the past decade, we have learned that the immunologic processes leading to allergic rhinitis and atopic asthma are the same. A large number of studies have examined the composition of inflammatory cell infiltrates in the nasal and bronchial mucosa of patients with allergic rhinitis and asthma. Critical cells that have been consistently identified in both upper and lower airway tissue include both resident (epithelial cells, mast cells, dendritic cells) and infiltrating cell types (eosinophils, Th 2 cells).
Allergen provocation studies have also demonstrated striking similarities between immunopathologic processes in the nasal and bronchial mucosa, including allergen-induced infiltration by inflammatory cells, cellular activation, and cytokine and chemokine expression or production. In addition, the development of early- and late-phase reactions and the acquisition of airway hyperresponsiveness have been convincingly demonstrated in both the nasal and the lower airways after allergen provocation.
Histologic studies of individuals with allergic rhinitis and no evidence of clinical asthma consistently demonstrate abnormalities of the bronchial mucosa, including thickening of the lamina reticularis and mucosa eosinophilia. These abnormalities are generally less pronounced than those of asthmatic patients, but sometimes, the findings in subjects with rhinitis are indistinguishable from those in subjects with mild asthma. A recent investigation of this phenomenon confirmed that airway inflammation in allergic rhinitis is midway between normal controls and asthmatics and that asthmatics have much lower levels of interferon gamma than these other two groups, indicating that this cytokine may be an important regulator of the asthma phenotype. Findings from these and other histologic studies demonstrate that both the upper and lower airways are histologically and functionally abnormal in patients with rhinitis and no asthma and that select cytokines may determine which patients manifest clinical signs and symptoms of asthma.
Effects of Rhinitis Therapy on Asthma
Physicians often note anecdotally that treatment of allergic nasal disease results in improvements in asthma symptoms and pulmonary function. However, there have been relatively few well-controlled, large-scale clinical trials that have attempted to quantify this effect.
Intranasal Corticosteroids
Intranasal corticosteroids (INS) are widely recognized as the most effective pharmacotherapy for allergic rhinitis, with potent effects on symptoms, nasal physiology, and upper airway mucosal inflammation. Given the important pairing of nasal disease and asthma, it therefore stands to reason that treatment of rhinitis with INS might have a salutary effect on the lower airways. During the past 25 years, a large number of clinical trials have been conducted to determine the effects of INS on asthma outcomes. A recent systematic review and meta-analysis examined all prior studies of INS in patients with allergic rhinitis and concomitant asthma and identified a total of 18 randomized, controlled studies with 2162 patients for inclusion in the analysis. Asthma outcomes consisted of pulmonary function (including first second forced expired value (FEV 1 ) and domiciliary peak expiratory flow rate), measures of nonspecific bronchial responsiveness, asthma symptoms scores, asthma-specific quality of life, and rescue bronchodilator use. Statistical analysis of a subgroup of studies that compared INS with placebo demonstrated significant improvements in all the above parameters, including FEV 1 (standardized mean difference [SMD] = 0.31, 95% CI, 0.04–0.08) and asthma symptoms (SMD = −0.42, 95% CI, −0.53 to −0.30). Importantly, there were no significant changes in asthma outcomes when INS were added to orally inhaled corticosteroids, suggesting that the impact of INS on chronic lower airways symptoms may be strongest in patients who are not receiving adequate asthma therapy. While these data are helpful in assessing the effects of INS on daily asthma outcomes, such as lung function and symptoms, the studies included in the meta-analysis were not designed to examine the effects of nasal therapy upon asthma exacerbations.
In addition to the above-randomized studies, clinical data from large populations has been employed to assess the relationship between INS use and asthma exacerbations and asthma-related resource utilization. A nested case-control study was performed using claims records from 215,000 members, age 6 years and older, of a managed care organization in the United States. Patients with both allergic rhinitis and asthma were identified and assessed for types and numbers of prescriptions for these conditions along with hospital-based care (emergency room visits and hospitalizations) for asthma. Patients who had used INS had a significantly lower risk for both asthma-related emergency room treatment and hospitalization (adjusted odds ratios: ER, 0.75, 95% CI, 0.62–0.91; hospitalization, 0.56. 95% CI, 0.42–0.76). These data suggest that use of INS may have an effect on major exacerbations of asthma, although it is uncertain whether this is a direct effect of rhinitis therapy or may reflect better overall care of the asthmatic patient.
Both the randomized trials and large database analyses indicate the potential importance of INS in reducing both daily assessments of asthma control (symptoms, beta-agonist use, and pulmonary function in patients not receiving inhaled corticosteroids [ICS]) and asthma exacerbations. As most of the INS preparations that were used during the above studies have very limited systemic availability, it is unlikely that these effects were due to systemic effects of the glucocorticoids.
Antihistamines.
The presence of histamine in the lower airways has been correlated with bronchial obstruction, and histamine has long been thought to play a role in bronchial asthma. However, early studies of first-generation antihistamines in adolescents and adults showed minimal improvements in bronchial asthma, and initial small trials of second-generation antihistamines yielded mixed results. However, two recent large-scale clinical studies using an antihistamine alone and an antihistamine-decongestant combination both resulted in significant improvements in asthma control. Grant and colleagues demonstrated that seasonal symptoms of rhinitis and asthma were significantly attenuated in patients treated with cetirizine 10 mg once daily in a large group of adolescents and adult patients. In a second study using loratadine 5 mg plus pseudoephedrine 120 mg twice daily in patients with seasonal allergic rhinitis and asthma, Corren and colleagues demonstrated that asthma symptoms, peak expiratory flow rates, and FEV 1 were all significantly improved in patients taking active therapy. In reviewing data from these and similar trials, it is difficult to determine whether the salutary effects of antihistamines in asthma can be attributed to direct effects on lower airway physiology or to improvements in rhinitis. Because many of the currently available agents appear to have weak or transient effects on resting airway tone, benefits to the lower airway may be due to modulation of upper airway function.
In the nested case-control study of rhinitis therapy and asthma outcomes, the use of second-generation oral antihistamines was associated with a nonsignificant trend toward lower risk of asthma-related emergency room visits and hospitalization. However, there appeared to be a possible additive effect between second-generation antihistamines and INS in further lowering the probability of a major asthma-related event.
These studies demonstrate that treatment of rhinitis may result in improvements in a number of asthma outcomes and suggest that nasal disease contributes to the pathophysiology of asthma. Based on the data in these studies, treatment of rhinitis may reduce symptoms of mild asthma to such an extent that the requirement for asthma therapy may be reduced or even eliminated. While population-based analyses have also shown that major asthma exacerbations resulting in hospital care may be reduced by INS, these findings reflect an important association but do not prove cause and effect.
Pathophysiologic Connections Between Allergic Rhinitis and Asthma
Although there is increasing evidence that allergic rhinitis may influence the clinical course of asthma, the mechanisms connecting upper and lower airway dysfunction are not entirely understood. A variety of theories have been invoked, including both direct and indirect effects of nasal dysfunction on the lower airways.
Systemic Effects of Nasal Inflammation on the Lower Airways
Research over the past few years has demonstrated that several inflammatory mediators produced during allergic reactions may enter the systemic circulation. Experimental nasal allergen challenge has been shown to induce both peripheral blood eosinophilia and activation of peripheral blood leukocytes. It has been postulated that the net result of these various factors on the systemic circulation is the promulgation of inflammation in other sites. Braunstahl and colleagues performed a nasal provocation study, suggesting a link between systemic inflammation and changes in airway inflammation and function. Prior to and 24 hours after the nasal challenge, bronchial mucosal biopsies were performed that demonstrated that the number of eosinophils in the lower airway mucosa, as well as the expression of adhesion molecules, increased after nasal allergen challenge. Further supporting this interaction between the upper and lower airways, Braunstahl and colleagues also found increased inflammatory markers in the nasal mucosa following the instillation of allergen into the lower airways of subjects with allergic rhinitis. Given this emerging evidence, it is likely that systemic factors do play a critical role in the interaction between the upper and lower airways.
Impaired Mucosal Function
It has been shown that allergic inflammation in the respiratory mucosa results in impairment of the barrier function of the epithelium. It has been hypothesized that this alteration in epithelial integrity might then lead to increases in allergen uptake, synthesis of IgE, and ultimately involvement of the lower airways. Alternatively, impaired nasal mucosa may be more susceptible to viruses, resulting in an increase in allergic sensitization and subsequently more asthma ( Fig. 47.1 ).
Nasal-Bronchial Reflex
Early mechanistic studies investigated the effects of several mucosal irritants on lower airway function in normal human subjects. In 1969, Kaufman and Wright applied silica particles onto the nasal mucosa of individuals without lower airway disease and noted significant, immediate increases in lower airway resistance. Bronchospasm induced by nasal silica was blocked by both resection of the trigeminal nerve and systemic administration of atropine. Fontanari and coworkers recently reevaluated the possibility of a neural connection between the upper and lower airways by using cold, dry air as the nasal stimulus. These investigators demonstrated that nasal exposure to very cold air caused an immediate and profound increase in pulmonary resistance that was prevented by both topical nasal anesthesia and cholinergic blockade induced by inhalation of ipratropium bromide. Both these studies strongly suggest the presence of a reflex involving irritant receptors in the upper airway (afferent limb) and cholinergic nerves in the lower airway (efferent limb).
Subsequent studies used challenge materials considered to be more biologically relevant to allergic rhinitis, including histamine, whole pollen particles, and allergen extracts. Yan and Salome performed nasal histamine challenges in subjects with perennial rhinitis and stable asthma and observed that FEV 1 was reduced by 10% or more immediately after provocation in 8 of 12 subjects. Importantly, radiolabeling studies were performed as part of this study that demonstrated that histamine was not deposited into the lower airways. However, other studies that used histamine or allergen failed to demonstrate bronchoconstriction after nasal provocation. This discrepancy in results may be partly explained by the type of patients who participated in these studies. Whereas Yan and Salome investigated subjects with perennial, symptomatic nasal disease, the majority of other studies examined asymptomatic patients outside their pollen season. Certainly, a substantial degree of heterogeneity exists between patients in their lower airway response to nasal stimulation.
In addition to neurally mediated bronchospasm, it has been postulated that a nasal allergic reaction might result in an alteration in lower airway responsiveness. Corren and colleagues investigated the effects of nasal allergen provocation on nonspecific bronchial responsiveness to methacholine. Ten subjects with seasonal allergic rhinitis and asthma were selected for study; all patients related worsening of their asthma to the onset of hay fever symptoms. Nonspecific bronchial responsiveness was significantly increased 30 minutes after nasal challenge and persisted for 4 hours.
Because radionuclide studies demonstrated no evidence of allergen deposition into the lungs, it seems unlikely that these increases in airway reactivity can be attributed to direct effects of allergen. In addition, the rapidity with which these changes occurred suggests the possibility of a reflex mechanism.
Mouth Breathing Caused by Nasal Obstruction
Nasal blockage resulting from tissue swelling and secretions may cause a shift from the normal pattern of nasal breathing to predominantly mouth breathing. Previous work has shown that mouth breathing associated with nasal obstruction resulted in worsening of exercise-induced bronchospasm, whereas exclusive nasal breathing significantly reduced asthma after exercise. Improvements in asthma associated with nasal breathing may be the result of superior humidification and warming of inspired air before it reaches the lower airways. Similarly, it would be expected that airborne allergens and pollutants would also be less likely to enter the lungs during periods of normal nasal function.
Postnasal Drip of Inflammatory Material
Patients frequently complain that postnasal drip triggers episodes of coughing and wheezing. Early studies investigating the possibility of aspiration of nasal secretions demonstrated that substances placed in the upper respiratory tract could later be recovered from the tracheobronchial tree. More recently, Huxley and colleagues investigated pharyngeal aspiration during sleep both in healthy subjects and in patients with depressed sensorium. With the use of a radiolabeled marker that was intermittently released into the nose, pulmonary aspiration was detected in a significant number of both the normal and the ill subjects. In a more recent and definitive investigation, however, Bardin and colleagues were unable to document significant aspiration of radionuclide in a study of 13 patients with chronic rhinosinusitis (CRS) and asthma.
It is difficult to determine which of these experimental mechanisms is most important in linking the nose to the lower airways. In all likelihood, however, several of these phenomena may contribute in some way to alterations in lung physiology in patients with allergic rhinitis and asthma.
Diagnostic and Therapeutic Implications
Diagnosis
The previously discussed data suggest that all patients with asthma be evaluated to determine the presence of concomitant chronic rhinitis. The patient should be questioned regarding types of symptoms, focusing on the presence of nasal congestion, sneezing, itching, discharge, and postnasal drip. Other associated symptoms (e.g., snoring, poor sleep quality, and ear congestion or popping) should also be investigated and considered when choosing therapy. The upper airway should then be carefully examined, with an emphasis on the size and vascularity of the nasal turbinates, type and presence of nasal secretions, tonsillar size, and color and elasticity of the tympanic membranes.
While allergic rhinitis is the most common form of chronic rhinitis in children (older than 2 years of age) and adolescents, a smaller number of patients will have chronic nonallergic rhinitis or CRS without allergy as the cause of their symptoms ( Table 47.1 ). Some children with CRS have concomitant allergy and may have symptoms and signs of both conditions. Much less likely is the possibility of a structural problem resulting in obstruction. In children, this is most likely to be a foreign body, such as a peanut or small piece of toy, which is inserted into the nose and causes unilateral nasal blockage and discharge with sneezing; occasionally, this is followed by a secondary sinus infection. Bony or cartilaginous problems (such as a deviated nasal septum) are unusual and most likely the result of trauma.
| Allergic Rhinitis | Nonallergic Rhinitis | Chronic Rhinosinusitis | |
|---|---|---|---|
| Nasal congestion | Mild-severe | Usually severe | Mild-severe |
| Sneezing | Mild-severe | None | None |
| Pruritis | Mild-severe | None | None |
| Watery discharge | Mild-severe | Mild-severe | None |
| Purulent discharge | None | None | Mild-severe |
| Eye symptoms | Mild-severe | None | None |
| Periorbital darkening | Mild-severe | Mild-severe | Mild-severe |
| Headache/pressure | None-mild | None-mild | Mild-severe |
Regarding diagnostic testing in patients with persistent rhinitis and asthma, allergy skin tests or in vitro measures of specific IgE should be performed using a panel of common airborne allergens. At a minimum, these should include house dust mites ( Dermatophagoides farinae and D. pterynissinus ), cockroaches, animal dander types (cat and dog), indoor and outdoor molds (Penicillium, Aspergillus, Cladosporium, and Alternaria), and regional pollens. This information is critical in differentiating allergic rhinitis from nonallergic disease or CRS and establishing an appropriate program of environmental control measures. Other tests, including total serum IgE level, microscopic analysis for nasal cytology, and total circulating blood eosinophils, have not proven helpful in either differentiating allergic rhinitis from other nasal disorders or in assessing the severity of the problem.
Allergen Avoidance
Once allergy testing is complete, the physician may devise a comprehensive program of allergen avoidance. The effects of environmental control strategies have been most heavily studied regarding dust mites and furry pets ( Box 47.1 ). Compliance with these measures may be difficult, but they will certainly be helpful in many patients with hypersensitivity to these allergens.
House Dust Mites
Weekly washing of all bedding in hot water (>130°F)
Weekly vacuum cleaning of all floor surfaces, using high-efficiency particulate air (HEPA)-type vacuum cleaner or standard vacuum cleaner with double-thickness reservoir bag
Removal of carpeting, or treatment of carpeting every 2–3 months with acaricidal spray or powder
Animal Danders (Any Furry Pet)
Optimal—Removal of the animal from indoor environment, followed by replacement of carpeting and aggressive housecleaning
Possibly effective—Keeping the cat indoors and instituting the following measures: Noncarpeted floors
Plastic or leather furniture
Frequent vacuum cleaning of floors
High-flow air filtration
Frequent cat bathing
Indoor Mold
Thorough eradication of infestation
Repair of source of water intrusion
Cockroach
Appropriate handling and storage of food and garbage
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