Allergic Rhinitis
Anthony J. Ricketti
Dennis J. Cleri
Introduction and Definitions
The clinical definition of allergic rhinitis is a symptomatic disorder of the nose induced by an immunoglobulin E (IgE)-mediated inflammatory reaction after allergen exposure of the membranes lining the nose (1). The symptoms that characterize the disorder are rhinorrhea, nasal congestion, sneezing, nasal pruritus, post-nasal drainage, and at times, pruritus of the eyes, ears, and throat.
Previously, allergic rhinitis was subdivided, based on the time of exposure into either a seasonal or a perennial disorder. Perennial allergic rhinitis is most frequently caused by indoor allergens such as dust mites, mold spores, animal danders, and cockroaches. Seasonal allergic rhinitis is related to a wide variety of pollens and molds. However, it became evident that a new classification system was required because of several clinical observations (2):
In many areas of the world, pollens and molds are perennial allergens (e.g., the weed Parietaria pollen allergy in the Mediterranean area [ 3]; and grass pollen allergy in southern California and Florida) ( 4).
Symptoms of perennial allergic rhinitis may not always be present throughout the year.
Many patients who are sensitive to pollen and also allergic to mold may have difficulty defining a pollen season ( 5).
The majority of patients are sensitized to several allergens and therefore manifest symptoms not only seasonally but throughout the year ( 6).
The 2001 Allergic Rhinitis and its Impact on Asthma (ARIA) workshop guidelines for the classification and treatment of allergic rhinitis ( 8) have led to the definitions of allergic nasal disease as intermittent or persistent, and mild or moderate-severe (2). Intermittent rhinitis is defined on the basis of symptoms that are present for fewer than 4 days per week or fewer than 4 weeks (2). When symptoms are present for more than 4 days per week and are present for more than 4 weeks, it is defined as persistent rhinitis. Mild symptoms do not affect sleep, impair participation in daily activities, sports, and leisure, or interfere with work or school and are not considered bothersome (2). Conversely, moderate-severe symptoms result in abnormal sleep, interfere with daily activities, sports, and leisure, impair work and school activities, and are considered troublesome. Any one of the designators classifies allergic rhinitis into the moderate-severe category (2).
Epidemiology
Although allergic rhinitis may have its onset at any age, the incidence of onset is greatest in children at adolescence, with a decrease in incidence seen in advancing age. The prevalence of allergic rhinitis has been estimated to be between 15% and 20% ( 9), but physician-diagnosed allergic rhinitis in the pediatric age group has been reported in as many as 42% ( 10). Although it has been reported in infants (11), in most cases, an individual requires two or more seasons of exposure to a new antigen before exhibiting the clinical manifestations of allergic rhinitis. Older children have a higher prevalence of allergic rhinitis than younger ones, with a peak occurring in children aged 13 to 14 years. Approximately 80% of individuals diagnosed with allergic rhinitis will develop symptoms before the age of 20 years (12). Boys tend to have an increased incidence of allergic rhinitis in childhood, but the sex ratio becomes equal in adulthood.
Epidemiology studies suggest that the prevalence of allergic rhinitis in the United States and around the world is increasing ( 13). However, accurate estimates of allergic rhinitis are difficult to obtain secondary to variability of geographic pollen counts, misinterpretation of symptoms by patients, and inability of the patient and physician to recognize the disorder. Although there is an increased prevalence of allergic rhinitis, the cause for this increase is unknown. Risk factors associated with development of allergic rhinitis include family history ( 14), higher socioeconomic status ( 15), atmospheric pollution ( 16), ethnicity other than white ( 17), late entry into daycare ( 18), lack of other siblings ( 19), birth during a pollen season (20), heavy maternal smoking during the first year of life (21), exposure to high concentrations of indoor allergens, such as mold spores, dust mites, and animal dander ( 22), higher serum IgE (>100 IU/mL before age 6 years) (21), presence of positive allergen skin-prick tests (23), early introduction of foods or formula (21), and a trend toward sedentary life styles ( 24).
Burden of Disease
According to 1997 survey data from primary care physicians, there were 16.9 million office visits for symptoms suggestive of allergic rhinitis ( 25). In 2000, more than $6 billion was spent on prescription medications for this condition and over-the-counter medications were at least twice that amount (26). In addition to the characteristic nasal and ocular symptoms of allergic rhinitis, patients can also experience fatigue; headache; disrupted sleep patterns; and declines in cognitive processing, psychomotor speed, verbal learning, and memory (27). Hidden direct costs include the treatment of asthma, upper respiratory infection, chronic sinusitis, otitis media, nasal polyposis, and obstructive sleep apnea (28). Surveys report that 38% of patients with allergic rhinitis have coexisting asthma, and as many as 78% of patients with asthma also have allergic rhinitis (29). Asthma and allergic rhinitis are often thought of as conditions that characterize different points on a continuum of inflammation within one common airway (30). Evidence suggests a common pathophysiology for these allergen-induced disorders and supports the observation that treatment of allergic rhinitis reduces the incidence and severity of asthma ( 31). Allergy has been linked as a contributing factor in 40% to 80% of cases of chronic sinusitis ( 32). Approximately 21% of children with nasal allergies experience otitis media with effusion (OME). Children with an OME have a 35% to 50% incidence of allergy ( 33, 34). In patients with allergic rhinitis, an allergen challenge induces expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for 90% of human rhinoviruses ( 32), increasing the susceptibility for an upper respiratory infection. In turn, rhinovirus can accentuate the pattern of airway reactivity in patients with allergic rhinitis ( 35). Although the link between allergic rhinitis and nasal polyps is considered controversial, the recurrence rate of nasal polyps in patients with allergic rhinitis is higher than for patients who are nonallergic (36). The indirect costs of allergic rhinitis such as absenteeism and presenteeism (decreased productivity while at work) are also substantial. Allergic rhinitis results in impaired productivity and/or missed work in 52% of patients (37). In a survey of 8,267 U.S. employees, 55% experienced allergic rhinitis symptoms for an average of 52.5 days, were absent from work for 3.6 days/year because of their condition, and were unproductive 2.3 hours/workday when experiencing symptoms. The mean total productivity (absenteeism and presenteeism) losses were $593/employee per year (38). In total, allergic rhinitis results in an estimated 3.5 million lost work days and 2 million lost school days (39). Approximately 10,000 children are absent from school on any given day secondary to allergic rhinitis (39). Depending on a child’s age, absence from school also may affect parents’ productivity or absence from work.
Quality-of-life surveys have evaluated the impairment secondary to allergic rhinitis. In the Medical Outcomes Study Short-Form Health Survey, of 36 items (SF-36) administered to patients with allergic rhinitis and asthma ( 40), patients with allergic rhinitis had similar impairment with asthma when evaluating energy/fatigue, general health perception, physical role limitiations as well as emotional role limitations—mental health, pain, and change in health. Patients with allergic rhinitis actually had significantly lower scores than asthma patients in the area of social functioning. These surveys clearly demonstrate the overall morbidity of the disorder and, therefore, the symptoms of these patients should not be trivialized.
Genetics
The hereditary character of allergic rhinitis and other atopic diseases has been frequently demonstrated in families and twins (41). In a series of 8,633 5-year-old twins in which the prevalence of rhinitis was 4.4%, there was a 93% correlation in full-term monozygotic twins having rhinitis (41). The correlation was 53% in dizygotic twins (41). The influence of environmental factors therefore is small.
Atopy has been linked to multiple genetic loci, including those on chromosomes 2, 5, 6, 7, 11, 13, 16, and 20 (42). A family history, therefore, represents a major risk factor for allergic rhinitis. In one study, development of atopic disease in the absence of parental family history was only present in 17%, whereas when one parent or sibling was atopic, the risk increased to 29%. When both parents were atopic, the risk for developing an atopic disorder was 47% in the next generation ( 43).
Etiology
Pollen and mold spores are the allergens responsible for intermittent or seasonal allergic rhinitis (Table 26.1). The pollens important in causing allergic rhinitis are from plants that depend on the wind (anemophilous pollens). Many grasses, trees, and weeds produce lightweight pollen in sufficient quantities to sensitize genetically susceptibile individuals. Plants that produce entomophilous pollens depend on insect pollination, and include golden rod, dandelions, and most other plants with obvious flowers, that do not cause allergic rhinitis symptoms. The pollination season of various plants depends on the individual plant and on the various geographic locations. For a particular plant in a given locale, however, the relative amount of night and day determines the pollinating season and it is constant from year to year. Weather conditions, such as temperature and rainfall, influence the amount of pollen produced but not the actual onset or termination of a specific season. Some of the effects of global warming appear to be lengthening some pollen seasons and increasing concentration of CO2, which can result in greater recoveries of ragweed pollen.
Table 26.1 Major Aeroallergens in Allergic Rhinitis | ||
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Ragweed pollen, a significant cause of allergic rhinitis, produces the most severe and longest seasonal rhinitis in the eastern and midwestern portions of the United States and Ontario, Canada. In those areas, ragweed pollen appears in significant amounts from the second or third week of August through September. Occasionally, sensitive patients may exhibit symptoms as early as the first few days of August, when smaller quantities of pollen first appear. Although ragweed is the dominant airborne allergen in North America during the late summer and early fall, there are also other important weed pollens, such as sheep sorrell in the spring and plantain in the summer months. Western ragweed and marsh elder in the western states, sagebrush and franseria in the Pacific areas, and careless weed, pigweed, and franseria in the southwestern United States are important allergens in the late summer and early fall. In the northern and eastern United States, the earliest pollens to appear are tree pollens, usually in March, April, or May. Grass pollens, which appear from May to late June or early July, cause allergic rhinitis in this locale. About 25% of pollinosis patients have both grass and ragweed allergic rhinitis, and about 5% have tree, grass, and ragweed allergies. In other geographic regions, these generalizations are not accurate, because of the particular climate and because some less common plants may predominate. For example, grass pollinates from early spring through late fall in the southwestern regions and accounts for allergic rhinitis that is almost perennial. In Southern California, grass pollen can be detected in all months except January, although the specific “grass” season is from April to September.
Airborne mold spores, the most important of which throughout the United States are Alternaria and Cladosporium species, also cause seasonal allergic rhinitis. Warm, damp weather favors the growth of molds and thereby influences the severity of the season. Generally, molds first appear in the air in the spring, become most significant during the warmer months, and usually disappear with the first frost. Thus, patients with marked hypersensitivity to molds may exhibit symptoms from early spring through the first frost, whereas those with
a lesser degree of hypersensitivity only may have symptoms from early summer through late fall.
a lesser degree of hypersensitivity only may have symptoms from early summer through late fall.
Inhalant allergens are the most important cause of perennial allergic rhinitis. The major perennial allergens are house dust mites, mold antigens (i.e., Aspergillus and Penicillium species), animal danders, cockroaches, and feather pillows which harbor dust mites. Occasionally, perennial allergic rhinitis may be the result of exposure to an occupational allergen. Symptoms tend to be perennial but not constant because there is a clear, temporal association with workplace exposure. Some causes of occupational rhinitis include laboratory animals (rats, mice, guinea pigs, etc.), grains (bakers and agricultural workers), medications such as psyllium or penicillin, wood dust, particularly hard woods (mahogany, Western red cedar, etc.), latex, and chemicals (acid anhydrides, platinum salts, glues, and solvents) (44).
Although some clinicians believe that food allergens may be significant factors in the cause of persistent allergic rhinitis, a direct immunologic relationship between ingested foods and persistent rhinitis symptoms has been difficult to establish. Rarely, hypersensitivity to dietary proteins may induce the symptoms of nonseasonal allergic rhinitis. Double-blind food challenges usually confirm such reactions (45). Cow’s milk has been the food often suspected of precipitating or aggravating upper respiratory symptoms. Usually, however, the overwhelming majority of patients with proven food allergies exhibit other symptoms, including gastrointestinal disturbances, urticaria, angioedema, asthma, and anaphylaxis, in addition to rhinitis, after ingestion of the specific food.
Cross-reactive allergens between food and inhalant allergens are common. Patients with allergic rhinitis due to birch and, to a lesser extent, other Betulaceae (hazel, alder) pollen frequently develop oral allergic symptoms to tree nuts, fruits, and vegetables, including apples, carrots, celery, and potatoes (46). Most patients develop mild symptoms but anaphylaxis may occur very rarely from these cross-reacting foods. Some birch or hazel pollen allergens cross-react with those of fresh apples, especially those located just beneath the skin. Baked apples are tolerated as is apple sauce (47). Ragweed-sensitive individuals may experience symptoms when eating banana or melon. Latex-sensitive individuals may develop symptoms when ingesting avocado, banana, chestnut, kiwi fruit, or other foods (48).
Nonspecific irritants and infections may influence the course of persistent (perennial) allergic rhinitis. Children with this condition appear to have a higher incidence of respiratory infections that tend to aggravate the condition and may lead to the development of complications. Irritants such as tobacco smoke, and air pollutants (sulfur dioxide, volatile organic compounds (49), particulate matter, ozone, diesel exhaust particles, nitrogen dioxide) can aggravate the symptoms. Drafts, chilling, and sudden changes in temperature also tend to do so. These features indicate that the patient has concurrent nonallergic rhinitis.
Clinical Features
The major symptoms of allergic rhinitis are sneezing, rhinorrhea, nasal pruritus, and nasal congestion, although patients may not have the entire symptom complex. When taking a history, one should record the specific characteristics of the symptoms, as follows:
Define the onset and duration of symptoms and emphasize any relationship to seasons or life events, such as changing residence or occupation, or acquiring a new pet.
Define the current symptoms including secretions, degree of congestion, sneezing, and nasal itching, or sinus pressure and pain. Obtain a history regarding ocular symptoms, such as itching, lacrimation, puffiness, and chemosis; pharyngeal symptoms of a mild sore throat, throat clearing, and itching of the palate and throat; and associated systemic symptoms of malaise, fatigue, or sleep disturbances.
Identify exacerbating factors, such as seasonal or perennial allergens and nonspecific irritants (e.g., cigarette smoke, chemical fumes, cold air, etc.).
Identify other associated allergic diseases, such as asthma or atopic dermatitis, or a family history of allergic diathesis.
Obtain a complete medication history, including both prescription and over-the-counter medications.
Sneezing is the most characteristic symptom, and occasionally one may have paroxysms of 10 to 20 sneezes in rapid succession. Sneezing episodes may arise without warning, or they may be preceded by an uncomfortable itching or irritated feeling in the nose. Sneezing attacks result in tearing of the eyes because of activation of the nasal-lacrimal reflex. During the pollen season, nonspecific factors, such as dust exposure, sudden drafts, air pollutants, or noxious irritants, may also trigger violent sneezing episodes.
The rhinorrhea is typically a thin discharge, which may be quite profuse and continuous. Because of the copious nature of the rhinorrhea, the skin covering the external nose and the upper lip may become irritated and tender. Purulent discharge is never seen in uncomplicated allergic rhinitis, and its presence usually indicates secondary infection. Nasal congestion resulting from swollen turbinates is a frequent complaint. Early in the season, the nasal obstruction may be more troublesome in the evening and at night, only to become almost continuous as the season progresses. If the nasal obstruction is severe, interference with aeration and drainage of the paranasal sinuses or the eustachian tube may occur,
resulting in complaints of headache or earache. The headache is of the so-called vacuum type, presumably caused by the development of negative pressure when air is absorbed from the obstructive sinus or middle ear. Patients also complain that their hearing is decreased and that sounds seem muffled. Patients may also notice a crackling sensation in the ears, especially when swallowing. Nasal congestion alone, particularly in children, occasionally may be the major or sole complaint. With continuous severe nasal congestion, the senses of smell and taste may be lost. Itching of the nose may also be a prominent feature, inducing frequent rubbing of the nose, particularly in children. Eye symptoms (pruritus, erythema, and lacrimation) often accompany the nasal symptoms. Patients with severe eye symptoms often complain of photophobia, inability to wear contact lenses, and sore, “tired” eyes. Conjunctival injection and chemosis often occur. There is marked itching of the ears, palate, throat, or face, which may be extremely annoying. Because of irritating sensations in the throat and the posterior drainage of the nasal secretions, a hacking, nonproductive cough may be present. A constricted feeling of the chest with associated dyspnea may occur suggesting coexistent asthma. Some patients have systemic symptoms of seasonal allergic rhinitis. Complaints may include weakness, malaise, irritability, fatigue, and anorexia. Certain patients relate that nausea, abdominal discomfort, and poor appetite appear to occur with swallowing excess mucous.
resulting in complaints of headache or earache. The headache is of the so-called vacuum type, presumably caused by the development of negative pressure when air is absorbed from the obstructive sinus or middle ear. Patients also complain that their hearing is decreased and that sounds seem muffled. Patients may also notice a crackling sensation in the ears, especially when swallowing. Nasal congestion alone, particularly in children, occasionally may be the major or sole complaint. With continuous severe nasal congestion, the senses of smell and taste may be lost. Itching of the nose may also be a prominent feature, inducing frequent rubbing of the nose, particularly in children. Eye symptoms (pruritus, erythema, and lacrimation) often accompany the nasal symptoms. Patients with severe eye symptoms often complain of photophobia, inability to wear contact lenses, and sore, “tired” eyes. Conjunctival injection and chemosis often occur. There is marked itching of the ears, palate, throat, or face, which may be extremely annoying. Because of irritating sensations in the throat and the posterior drainage of the nasal secretions, a hacking, nonproductive cough may be present. A constricted feeling of the chest with associated dyspnea may occur suggesting coexistent asthma. Some patients have systemic symptoms of seasonal allergic rhinitis. Complaints may include weakness, malaise, irritability, fatigue, and anorexia. Certain patients relate that nausea, abdominal discomfort, and poor appetite appear to occur with swallowing excess mucous.
A characteristic feature of the symptom complex is the periodicity of its appearance. Symptoms usually recur each year for many years in relation to the duration of the pollinating season of the causative plant. The most sensitive patients exhibit symptoms early in the season, almost as soon as the pollen appears in the air. The intensity of the symptoms tends to follow the course of pollination, becoming more severe when the pollen concentration is highest and waning as the season ends, when the amount of pollen in the air decreases. In some patients, symptoms disappear suddenly when the pollination season is over, whereas in others, symptoms may disappear gradually over a period of 2 to 3 weeks after the pollination season is completed. There may be an increased reactivity of the nasal mucosa after repeated exposure to the pollen. This local and nonspecific increased reactivity has been termed the priming effect ( 50). Under experimental conditions a patient may respond to an allergen not otherwise considered clinically significant if he or she had been exposed or primed to a clinically significant allergen. The nonspecificity of this effect may account for the presence of symptoms in some patients beyond the termination of the pollinating season because an allergen not clinically important by itself may induce symptoms in the “primed” nose. For example, a patient with positive skin tests to mold antigens and ragweed, and no symptoms until August may have symptoms until late October, after the ragweed-pollinating season is over. The symptoms persist because of the presence of molds in the air, which affect the primed mucous membrane. In most patients, however, this does not appear to occur ( 51). The presence of a secondary infection, or the effects of nonspecific irritants on inflamed nasal membranes, may also prolong and influence the degree of rhinitis symptoms beyond the specific pollinating season. Some nonspecific irritants include tobacco smoke, paints, newspaper ink, and soap powders. Rapid atmospheric changes may aggravate symptoms in predisposed patients. Nonspecific air pollutants may also potentiate the symptoms of allergic rhinitis, such as sulfur dioxide, ozone, carbon monoxide, and nitrogen dioxide.
These symptoms of allergic rhinitis may exhibit periodicity within the season. Many patients tend to have more intense symptoms in the morning because most windborne pollen is released in greatest numbers between sunrise and 9:00 AM. Some specific factors such as rain may decrease symptoms of rhinitis because rain can clear pollen from the air. Also, dry windy days may increase symptoms because higher concentrations of pollen may be distributed over larger areas.
The symptoms of perennial allergic rhinitis are similar to seasonal rhinitis. The decreased severity of symptoms seen in some patients may lead them to interpret their symptoms as resulting from “sinus trouble” or “frequent colds.” Nasal congestion may be the dominant symptom, particularly in children, in whom the passageways are relatively small. Sneezing; clear rhinorrhea; itching of the nose, eyes, ears, and throat; and lacrimation may also occur. The presence of itching in the nasopharyngeal and ocular areas is consistent with an allergic cause of the chronic rhinitis. The chronic nasal obstruction may cause mouth breathing, snoring, almost constant sniffing, and a nasal twang to the voice. The obstruction may worsen or be responsible for the development of obstructive sleep apnea. Because of the constant mouth breathing, patients may complain of a dry, irritated, or sore throat. Loss of the sense of smell may occur in patients with marked chronic nasal obstruction. Sneezing episodes on awakening or in the early morning hours are a complaint. Because the chronic edema involves the opening of the eustachian tube and the paranasal sinuses, dull frontal headaches and ear complaints, such as decreased hearing, fullness and popping of the ears, are common. In children, there may be recurrent episodes of serous otitis media. Chronic nasal obstruction may lead to eustachian tube dysfunction. Persistent, low-grade nasal pruritus leads to almost constant rubbing of the nose and nasal twitching. In children, recurrent epistaxis may occur because of the friability of the mucous membranes, sneezing episodes, forceful nose blowing, or nose picking. After exposure to significant levels of an allergen, such as close contact with a pet or when dusting the house, the symptoms may be as severe as in the acute stages of seasonal
allergic rhinitis. Constant, excessive postnasal drainage of secretions may be associated with a chronic cough or a continual clearing of the throat.
allergic rhinitis. Constant, excessive postnasal drainage of secretions may be associated with a chronic cough or a continual clearing of the throat.
Physical Examination
Most abnormal physical findings are present during the acute stages of seasonal allergic rhinitis. The physical findings commonly recognized include:
Nasal obstruction and associated mouth breathing
Pale to bluish nasal mucosa and enlarged (boggy) inferior tubinates
Clear nasal secretions (whitish secretions may be seen in patients experiencing severe allergic rhinitis)
Clear or white secretions along the posterior wall of the nasopharynx
Conjunctival erythema, lacrimation, and puffiness of the eyes
The physical findings, which are usually confined to the nose, ears, and eyes, aid in the diagnosis. Rubbing of the nose and mouth breathing are common findings. Some children will rub the nose in an upward and outward fashion, which has been termed the allergic salute. The eyes may exhibit excessive lacrimation. The sclera and conjunctivae may be reddened, and chemosis is often present. The conjunctivae may be swollen and may appear granular, and the eyelids are often swollen. The skin above the nose may be reddened and irritated because of the continuous rubbing and blowing. Examination of the nasal cavity discloses a pale, wet, edematous mucosa, frequently bluish in color. A clear, thin nasal secretion may be seen within the nasal cavity. Swollen turbinates may completely occlude the nasal passageway and severely affect the patient. Nasal polyps may be present in individuals with allergic rhinitis. Occasionally, there is fluid in the middle ear, resulting in decreased hearing. The pharynx is usually normal. The nose and eye examination are normal during asymptomatic intervals.
In patients with perennial allergic rhinitis, the physical examination may aid in the diagnosis, particularly in a child, who may constantly rub his nose or eyes. These include a gaping appearance due to the constant mouth breathing, and a broadening of the midsection of the nose. There may be a transverse nasal crease across the lower third of the nose where the soft cartilagenous portion meets the rigid bony bridge. This is the result of the continual rubbing and pushing of the nose to relieve itching. The mucous membranes are pale, moist, and boggy, and may have a bluish tinge. Polyps may be present in cases of chronic perennial allergic rhinitis of long duration. Their characteristic appearance is smooth, glistening, and white. They may take the form of grapelike masses. However, polyps may also occur in patients without allergic rhinitis, and thus causality cannot be inferred. The nasal secretions are usually clear and watery, but may be more mucoid and microscopically may show large numbers of eosinophils. Dark circles under the eyes, known as allergic shiners, appear in some children. These are presumed to be due to venous stasis secondary to constant nasal congestion. The conjunctiva may be injected or may appear granular. In children affected with perennial allergic rhinitis early in life, narrowing of the arch of the palate may occur, leading to the Gothic arch. These children may develop facial deformities, such as dental malocclusion or gingival hypertrophy. The throat is usually normal on examination, although the posterior pharyngeal wall may exhibit prominent lymphoid follicles.
Pathophysiology
The nose has the following six major functions:
An olfactory organ
A resonator for phonation
A passageway for airflow in and out of the lungs
A means of humidifying and warming inspired air
A filter of noxious particles from inspired air
A part of the immunologic responses of the nose and sinuses (52)
Allergic reactions occurring in the nasal mucous membranes markedly affect the nose’s major functions. The nose can initiate immune mechanisms, and the significance of mediator release from nasal mast cells and basophils in the immediate-type allergic reaction is well established. Patients with allergic rhinitis have IgE antibodies that bind to high-affinity receptors (FCЄRI) on mast cells and basophils, and to low-affinity receptors (FCЄRII or CD23) on other cells, such as monocytes, eosinophils, B cells, and platelets. Sensitization to an allergen is necessary to elicit an IgE response. After inhalation, the allergen must first be internalized by antigen-presenting cells, which include macrophages, CD1+ dendritic cells, B-lymphocytes, and epithelial cells (53). After allergen processing, peptide fragments of the allergen are exteriorized and presented with class II (MHC) molecules of host antigen presenting cells to CD4+ T-lymphocytes. Nasal provocation with allergen has been associated with increases of such HLA-DR and HLA-DQ positive cells in the lamina propria and epithelium in allergic subjects (54). These lymphocytes have receptors specific for the particular MHC peptide complex. This interaction results in the release of cytokines by the CD4+ cell. The switch from the TH1 phenotype to the TH2 phenotype is the crucial early event in allergic sensitization and is key to the development of allergic inflammation. Allergic inflammation involves two major TH2-mediated pathways:
The secretion of interleukin-4 (IL-4) and IL-13 that results in isotypic switching of B lymphocytes to secrete IgE (55)
The secretion of eosinophil growth factor, IL-5 (72)
B-lymphocytes require two signals for isotypic switch to IgE (56). In the first signal, Il-4 or Il-13 stimulate transcription at the Ce locus, the site of exons that encode the constant region of the IgE heavy chain. Interaction of CD40 on the B-cell membrane with CD40 ligand on the surface of T-lymphocytes provides the second signal that activates genetic recombination in the functional IgE heavy chain. IL-4 and IL-13 also upregulate vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells promoting adhesion of inflammatory cell populations and facilitate their migration into areas of allergic inflammation.
After IgE antibodies specific for a certain allergen are synthesized and secreted, they bind to high-affinity receptors on mast cells. On nasal re-exposure to allergen, the allergen cross links the specific cell-bound IgE antibodies on the mast cell surface in a calcium-dependent process resulting in the release of a number of mediators of inflammation. Mediators released include histamine, leukotrienes, prostaglandins, platelet-activating factor, and bradykinin. These mediators are responsible for vasodilatation, increased vascular permeability, increased glandular secretion, and stimulation of afferent nerves, which culminate in the immediate-type rhinitis symptoms (57). Chemokines and cytokines are generated as well.
Mast cells are present in concentrations of 7,000/mm3 in the normal nasal submucosa but only 50/mm3 in the nasal epithelium. Some studies report increased mast cells in the nasal epithelium in allergic rhinitis. Nasal mast cells are predominantly located in the nasal lamina propria as connective tissue mast cells, although 15% are epithelial and are called mucosal mast cells. Mucosal mast cells express tryptase without chymase. They proliferate in allergic rhinitis under the influence of TH2 cytokines. The superficial nasal epithelium in patients with allergic rhinitis has 50-fold more mast cell and basophils when compared to the epithelium of nonallergic patients ( 58).
Mast cells and their mediators are central to the pathogenesis of the early response, as indicated by the demonstration of mast cell degranulation in the nasal mucosa and the detection of mast cell-derived mediators, including histamine, leukotriene C4 (LTC-4), and prostaglandin D2 (PGD2) in nasal washings. In addition to mast cell mediators, the early response is associated with an increase in neuropeptides, such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and increasing numbers of cytokines (IL-1, IL-3, IL-4, IL-5, IL-6, granulocyte macrophage colony-stimulating factor [GM-CSF]), and tumor necrosis factor-&aacgr; (TNF-&aacgr;) (59–63). The mast cell derived cytokines promote further IgE production, mast cell and eosinophil growth, chemotaxis, and survival. IL-5, TNF-&aacgr;, and IL-1 promote eosinophil movement by increasing the expression of adhesion molecules on endothelium. In turn, eosinophils secrete a plethora of cytokines including IL-3, IL-4, IL-5, IL-10, and GM-CSF resulting in mast cell growth and TH2 proliferation. Eosinophils may also function in an autocrine manner by producing cytokines IL-3, IL-5, and GM-CSF, which are important in hematopoiesis, differentiation, and survival of eosinophils. With continuation of allergic inflammation, one sees an accumulation of CD4+ lymphocytes, eosinophils, neutrophils, and basophils ( 64). Eosinophils release oxygen radicals and proteins including eosinophil major basic protein, eosinophil cationic protein, and eosinophil peroxidases. These proteins may disrupt the respiratory epithelium and promote further mast cell mediator release and hyperresponsiveness ( 65,66). There are strong correlations between the number of basophils and the level of histamine in the late reaction, and between the number of eosinophils and the amount of eosinophil major basic protein. These findings suggest that these cells may participate in allergic inflammation by not only entering the nose, but also degranulating ( 67, 68). Eosinophils increase during seasonal exposure, and the number of eosinophil progenitors in the nasal scrapings increases after exposure to allergens, and correlates with the severity of seasonal disease ( 69).
The infiltration of the nasal cavity with basophils, lymphocytes, eosinophils, and neutrophils characterizes the late-phase reaction of allergic rhinitis. The late-phase reaction will occur in approximately 50% of patients with allergic rhinitis who undergo nasal challenge. This reaction is associated with elevated levels of mediators similar to the immediate allergic reaction, except PGD2 and tryptase are not detected. The absence of the mast cell-derived mediators PGD2 and tryptase during the late-phase reaction is consistent with basophil-derived histamine release rather than mast cell involvement. Basophils are noted to be significantly increased in nasal lavage fluids 3 to 11 hours after allergen challenge, correlating their role in the late-phase reaction ( 68). CD4+ CD25 T-cells, in addition to neutrophils, eosinophils, and basophils, are increased during the late-phase response. These CD4 T-lymphocytes help promote the late-phase allergic reaction because they express messenger RNA for IL-3, IL-4, IL-5, and GM-CSF ( 70).
The heating and humidification of inspired air is an important function of the nasal mucosa. The highly vascularized mucosa of the turbinates in the septum provides an effective structure to heat and humidify air as it passes over them. The blood vessels are under the direction of the autonomic nervous system, which controls reflex adjustments for efficient performance of this function. The sympathetic nervous system provides for vascular constriction with a reduction of secretions. The parasympathetic nervous system enables vascular dilatation and an increase in secretions. This high degree of vascularization in the nasal cavity and the changes in the vasculature may lead to severe nasal obstruction (71). In most individuals under normal conditions, there is a
rhythmic alternating congestion and decongestion of the mucosa, referred to as the nasal cycle.
rhythmic alternating congestion and decongestion of the mucosa, referred to as the nasal cycle.
The protecting and cleansing role of the nasal mucosa is also an important function. Relatively large particles are filtered out of the inspired air by the hairs within the nostrils. The nasal secretions contain an enzyme, lysozyme, which is bacteriostatic. The pH of the nasal secretions remains relatively constant at 7. Lysozyme activity and ciliary action are optimal at this pH. Ciliated cells line the major portions of the nose, septum, and paranasal sinuses. The cilia beat at a frequency of 1,000 beats/min, producing a streaming mucus blanket at an approximate rate of 3 mm/min to 25 mm/min. The mucus is produced by mucus and serous glands, and epithelial goblet cells in the mucosa. The density of goblet cells in the nose and in the large airways is approximately 10,000/mm3 (72). The number of goblet cells and mucus glands does not appear to increase in chronic rhinitis ( 73). The mucus blanket containing the filtered materials moves toward the pharynx to be expectorated or swallowed.
Laboratory Findings
A characteristic laboratory finding in allergic rhinitis, also termed intermittent rhinitis (2), is the presence of large numbers of eosinophils in a Hansel-stained smear of the nasal secretions obtained during a period of symptoms. In classic seasonal allergic rhinitis, this test is usually not necessary to make a diagnosis. Its use is limited to questionable cases and more often in defining chronic allergic rhinitis.
In chronic rhinitis, the presence of large numbers of eosinophils suggests an allergic cause, although nonallergic rhinitis with eosinophilia syndrome (NARES) certainly occurs. The absence of nasal eosinophilia does not exclude an allergic cause, especially if the test is performed during a relatively quiescent period of the disease, or in the presence of bacterial infection when large numbers of polymorphonuclear neutrophils obscure the eosinophils.
Peripheral blood eosinophilia of <12% may or may not be present in active seasonal allergic rhinitis. A significantly elevated concentration of serum IgE may occur in some patients with allergic rhinitis, but many other conditions (including racial factors) may increase the serum levels of total IgE such as concomitant atopic dermatitis. Thus, the measurement of total serum IgE is barely predictive for allergy screening in rhinitis and should not be used as a diagnostic tool (1).
Diagnosis
The diagnosis of seasonal (intermittent) allergic rhinitis usually presents no difficulty by the time the patient has had symptoms severe enough to seek medical attention. The seasonal nature of the condition, the characteristic symptom complex, and the physical findings should establish a diagnosis in almost all cases. If the patient is first seen during the initial or second season, or if the major symptom is conjunctivitis, there may be a delay in making the diagnosis from the history alone. Additional supporting evidence is a positive history of allergic disorders in the immediate family and a collateral history of other allergic disorders in the patient. After the history is taken and the physical examination is performed, skin tests should be performed to determine the reactivity of the patient against the suspected allergens. For the proper interpretation of the meaning of a positive skin test, it is important to remember that patients with allergic rhinitis may exhibit positive skin tests to allergens other than those that are clinically important. In seasonal allergic rhinitis, it has been demonstrated that prick puncture testing with standardized extracts is adequate for diagnostic purposes in many patients if standardized extracts are used. Intradermal testing when positive may not always correlate with allergic disease ( 74,75). Skin testing should be performed and interpreted by trained personnel because results may be altered by the distance placed between allergens ( 76), the application site (back versus arm), the type of device used for testing ( 77), the season of the year tested ( 78), and the quality of extracts used for testing ( 79).
The first technique used to accurately measure serum specific IgE was the RAST (radioallergosorbent test) ( 80– 82). Newer techniques use enzyme-labeled anti-IgE. The in vitro tests have been employed as a diagnostic aid in some allergic diseases. RAST or enzyme-labeled anti-IgE assays of circulating IgE antibody can be used instead of skin testing when high-quality extracts are not available, when a control skin test with a diluent is consistently positive, when antihistamine therapy cannot be discontinued, or widespread skin disease is present.
Initially, RAST, then enzyme-based anti-IgE assays appear to correlate fairly well with other measures of sensitivity, such as skin tests, end-point titration, histamine release, and provocation tests. The frequency of positive reactions obtained by skin testing is usually greater than that found with serum or nasal RAST or enzyme assay (ImmunoCAP, Phadia). In view of these findings, the serum assays may be used as a supplement to skin testing. Skin testing is the diagnostic method of choice to demonstrate IgE antibodies. When the skin test is positive, there is little need for other tests. When the skin test is dubiously positive, the in vitro diagnostic test will, as a rule, be negative. Therefore, the information obtained by examining serum IgE antibody by in vitro test usually adds little to that gleaned from critical evaluation of skin testing with high-quality extracts.
Another procedure, nasal provocation, is a useful tool (83) but not as a generally recognized diagnostic procedure. Skin testing should be performed because, in contrast to the nasal test, the skin test is quick,
inexpensive, safe, and without discomfort. It has the additional advantage of possessing better reproducibility.
inexpensive, safe, and without discomfort. It has the additional advantage of possessing better reproducibility.
Differential Diagnosis
The diagnosis of allergic rhinitis must be established carefully since an incorrect diagnosis could result in expensive treatments and major alterations in a patient’s lifestyle and environment. Several medical conditions may be confused with persistent allergic rhinitis (Table 26.2). The main causes of persistent nasal congestion and discharge include rhinitis medicamentosa, drugs, pregnancy, nasal foreign bodies, other bony abnormalities of the lateral nasal wall, concha bullosa (air cell within the middle turbinate), enlarged adenoids, nasal polyps, cerebrospinal fluid rhinorrhea, tumors, hypothyroidism, ciliary dyskinesia from cystic fibrosis, primary ciliary dyskinesia, Kartagener syndrome, granulomatous diseases (i.e., sarcoidosis, Wegener granulomatosis, midline granuloma), nasal mastocytosis, congenital syphilis, gustatory rhinitis, gastroesophageal reflux, atrophic rhinitis, Churg-Strauss vasculitis, allergic fungal sinusitis, nonallergic rhinitis, or NARES.
Table 26.2 Differential Diagnosis of Nonallergic rhinitis | |||||||
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Rhinitis Medicamentosa
A condition that may enter into the differential diagnosis is rhinitis medicamentosa, which results from the overuse of decongestant (vasoconstricting) nose drops. Every patient who presents with the complaint of chronic nasal congestion should be carefully questioned as to the amount and frequency of the use of nose drops.
Drugs
Patients taking antihypertensive medications such as β-adrenergic blockers, α-adrenergic blockers, hydralazine, alpha methyldopa, erectile dysfunction medications, and certain psychoactive drugs may complain of marked nasal congestion, which is a common side effect of these agents. Discontinuation of these drugs for a few days results in marked symptomatic improvement.
Cyclic changes in rhinitis intensity may be related to the changes in relative concentrations of the complex mix of hormones during the menstrual cycle. In nasal provocation experiments, allergic patients on oral contraceptives having grass challenges had less nasal congestion at day 14 of the menstrual cycle and more sneezing at the end of the cycle (84). Thus, oral contraceptives affect nasal reactivity in complex ways and usually can be continued in patients with allergic rhinitis.
Cocaine sniffing is often associated with frequent sniffing, rhinorrhea, diminished olfaction, and septal perforation ( 85).
Related posts:
Immunology of IgE-mediated and Other Hypersensitivity Responses
Physiologic and Biologic Evaluation of Allergic Lung Diseases
Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis
Management of Acute Severe Asthma
Nasal Polyposis, Sinusitis, and Nonallergic Rhinitis
Eosinophilic Esophagitis
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