Chapter 62 Seasonal and Acute Allergic Reactions
Allergic rhinitis is the most common atopic disease. Although the prevalence varies by region, it is estimated that nearly 25% of the population may be affected.8 It is the second most prevalent chronic condition in the United States, outranked only by hypertension.72 Allergic rhinitis may be classified as seasonal (commonly referred to as hay fever) or perennial. The seasonal form is caused by aeroallergens released from the pollens of wind-pollinated plants, which include trees, grasses, and weeds. Perennial symptoms are commonly the result of exposure to house dust mites, domestic pets, cockroaches, and mold. In temperate climates, sufferers of perennial allergic rhinitis with a seasonal component often experience worsening symptoms during the warmer months because of the additional burden of seasonal allergens.
Although anaphylaxis is not as common as allergic rhinitis, it represents the most severe form of allergic reaction and can lead to a serious, including fatal, outcome if not treated promptly. The exact prevalence of anaphylaxis is not known. Based on extrapolation from data, the estimated risk for anaphylaxis per person in the United States is 1% to 3%.79 Anaphylactic reactions are probably underrecognized and underreported, particularly in cases of unexplained death. In one study, elevated tryptase levels, which are often found during acute anaphylaxis, were found in 13% of 68 patients postmortem.62 Foods and medications are the most common causes of anaphylaxis. Each year, approximately 40 deaths in the United States are attributed to anaphylaxis resulting from bee stings.2
Allergic rhinitis is a chronic immunoglobulin E–mediated (IgE-mediated) inflammatory disease of the nasal mucosa. It is the most common atopic disease, and for reasons not yet clear, its prevalence is increasing worldwide. The economic impact of allergic rhinitis is impressive. In 2002, the total direct and indirect costs were $7.3 billion and $4.2 billion, respectively.61 Indirect costs were mainly attributed to work or school absenteeism. In the United States, allergic rhinitis is responsible for 3.5 million lost work days and 2 million lost school days.61 The disease usually manifests in early childhood or adolescence and peaks in the second or third decade of life. The disease does not appear to favor any gender, ethnic group, or race. The most important risk factor for development of allergic rhinitis is a family history of atopy, especially with early onset of disease. In comparison with the general population, the risk is 30% greater if one parent or sibling is atopic, and 50% greater if both parents are affected.47 On the other hand, lack of complete concordance for atopy in identical twins emphasizes the importance of environmental factors in disease development.4 Allergic rhinitis, like other atopic conditions such as asthma and atopic dermatitis, tends to cluster in families.
The two important components in the pathogenesis of allergic rhinitis are the acute allergic reaction and late inflammatory events. Type I immediate hypersensitivity reaction accounts for most of the acute clinical manifestations of allergic rhinitis, and cells such as eosinophils, basophils, and T lymphocytes play important roles in late inflammatory events. Production of allergen-specific IgE (sensitization) antibodies forms the underlying basis of immediate hypersensitivity; atopy is defined as the genetic predisposition to develop allergen-specific IgE antibodies. The sensitization process requires a cooperative effort between CD4 T lymphocytes and B lymphocytes (Figure 62-1). It begins with presentation of an allergen to CD4 T lymphocytes by antigen-presenting cells (e.g., macrophages) in the context of a major histocompatibility complex. Cytokines released from CD4 T lymphocytes as a result of this interaction cause differentiation of B lymphocytes into immunoglobulin-secreting plasma cells. This differentiation leads to isotype switching (production of specific antibody types) within the plasma cells. For example, release of cytokine interleukin IL-4 or IL-13 from T lymphocytes promotes IgE switching.14 Once allergen-specific IgE antibody is produced, subsequent exposure and allergen binding to the IgE molecule on the surface of mast cells result in cross-linking of the IgE molecule. Consequently, mast cells or basophils degranulate and release preformed and newly synthesized mediators. The prototype preformed mediator is histamine, and the newly synthesized mediators include those of the arachidonic acid pathway (leukotrienes, prostaglandins, and platelet-activating factor), neuropeptides (e.g., substance P), and cytokines (e.g., IL-4, IL-5).
FIGURE 62-1 The natural history of allergic rhinitis (a simplified schematic). During phase 1, the individual becomes sensitized to an allergen. During phase 2, clinical disease develops. An overwhelming majority of individuals have an early response on re-exposure to the allergen. The activation of mast cells and release of mediators dominate the early response. After the early response, most individuals have cellular infiltration of the nasal mucosa, causing late inflammatory events, including the spontaneous recurrence of release of mediators (late-phase reaction), hyperresponsiveness to irritants, and increased responsiveness to the allergen (priming). Circles indicate the heterogeneity of these late inflammatory events. Inflammation can resolve spontaneously, cause a complication, or lead to an irreversible form of chronic rhinitis.
(From Naclerio R: Allergic rhinitis, N Engl J Med 325:860, 1991.)
Release of chemical mediators has various pathologic and clinical consequences. Sneezing and itching result from histamine stimulation of its receptors on sensory nerve endings. Rhinorrhea results from increased vascular permeability produced by all the mediators, and leukotrienes and prostaglandins are believed to play major roles in nasal congestion.74 Our knowledge of the pathophysiology of allergic rhinitis has been greatly enhanced by nasal challenge studies.26 It is now known that the allergic reaction consists of an early phase, characterized by mast-cell or basophil degranulation, and a late phase, which occurs 4 to 6 hours after the early phase (see Figure 62-1). The hallmark of the late-phase reaction is an influx of inflammatory cells, such as eosinophils, basophils, and T lymphocytes.3 For example, basophils cause further histamine release, and T lymphocytes release additional cytokines that enhance IgE production (via IL-4) and eosinophil activation (via IL-5). As a result of further inflammatory activity by these cells, there is recrudescence of symptoms many hours after the initial allergen exposure. Leukotrienes, prostaglandins, and cytokines released in the early-phase reaction play an important role in recruiting the late-phase cellular components to the inflammatory site. Although inhaled corticosteroids block both the early- and late-phase reactions, systemic corticosteroids block only the late-phase reaction.
Airborne allergens are the primary etiologic agents of allergic rhinitis. Although many potential allergenic proteins exist, relatively few are clinically important and even fewer have been isolated and characterized. Allergens are low-molecular-weight proteins or glycoproteins capable of eliciting a type I immediate hypersensitivity reaction (production of IgE antibodies). Allergens can be conveniently divided into those that exist in the outdoor environment and those that exist in the indoor environment. In the outdoors, pollens of trees, grasses, and weeds, and certain fungi (e.g., Alternaria and Cladosporium species) most commonly provoke symptoms. Pollen-sensitive individuals typically experience seasonal rhinitis in predictable time intervals from one season to the next. Although fungi are more ubiquitous in nature and do not have the distinct seasons that pollens have, both outdoor and indoor fungi thrive in moist and humid environments. Therefore in temperate climates, fungi counts start to rise in spring, with a peak in mid- to late summer. Indoor allergens include fungi, furred animals, cockroaches, and dust mites. Unlike outdoor allergens, which typically cause seasonal symptoms, indoor allergens often cause perennial symptoms. However, the symptoms are less drastic in nature, often making diagnosis more difficult.
Pollination in higher-order plants consists of transfer of the male gametophyte to the female gametophyte. In this process, pollen grains serve as vectors for male gametophytes. Of the different types of pollen-producing plants, flowering plants (including trees, grasses, and weeds) are the most important from an allergic standpoint. Flowering plants may be divided into those that rely on animal vectors (e.g., insects) for pollination (termed entomophilous) and those that depend on the wind (termed anemophilous). In general, only anemophilous plants (including trees, grasses, and weeds) cause allergic symptoms.67 Pollens of entomophilous plants do not achieve high airborne concentrations. In temperate climates, pollination of trees, grasses, and weeds occurs in predictable time intervals in a given region. Therefore it is important to know the relevant local botany and respective pollination seasons (Table 62-1 and Figure 62-2).
(From Sicherer SH, Eggleston PA: Environmental allergens. In Lieberman P, Anderson JA, editors: Allergic diseases: Diagnosis and treatment, Totowa, NJ, 1997, Humana.)
As shown in Figure 62-2, tree pollination marks the onset of allergy season in most parts of North America. It begins as early as mid-January in the Southwest or early April in the Northeast, and it terminates between early and late May. Trees of allergenic significance in various regions are listed in Table 62-1. Grass pollen, with its worldwide distribution, is a significant source of allergen exposure and a major cause of allergic rhinitis in sensitive individuals. In frost-free areas of North America, grass pollen may be present year-round, whereas in temperate climates, grass pollination peaks between mid-May and mid-July. Important grass types are rye, timothy, Kentucky bluegrass, orchard, Johnson, and Bermuda. Unlike ragweed and tree pollen allergens, grass pollen allergens show extensive cross-reactivity among different species, and allergic individuals are generally sensitive to many of these species. Weeds represent the final pollen producers of the season, typically generating pollen from mid-August through mid-October. Although a variety of weeds cause regionally significant allergies, ragweed is found in most parts of North America.
Numerous allergenic fungi are responsible for both seasonal and perennial symptoms. The three most important classes of allergic fungi are zygomycetes (e.g., Rhizopus, Mucor), basidiomycetes (e.g., rust, smut, Ganoderma), and ascomycetes (e.g., Cladosporium, Penicillium, Aspergillus, Alternaria, Epicoccum). Among the outdoor fungi, Cladosporium and Alternaria are the most abundant and cause significant symptoms in sensitive individuals. Although fungi can survive in various climates, they grow best in warm, humid environments. The peak fungal season in many areas is in mid- to late summer and fall, with a marked reduction after the first frost in temperate climates. Fungi levels may rise in spring, when decaying vegetation is uncovered after the snow has melted. Common outdoor sources of fungal growth are leaves, moist debris, and soil; therefore outdoor activities, such as raking, farming, and mowing, significantly increase exposure.
Dust mites are microscopic arachnids that are close relatives of ticks and spiders. They feed on human epidermal scales and, like fungi, prefer a warm, humid environment. Dust mites are the most common indoor allergens and can cause significant perennial symptoms in sensitive individuals. Although there is no good correlation between exposure level and degree of rhinitis symptoms, a level of 10 µg/g of dust is considered a risk factor for development of acute asthma symptoms.53 Common indoor sources of dust mite exposure include mattresses, pillows, blankets, upholstery, and stuffed toys. Dust mites may proliferate in sleeping bags stored in humid environments (e.g., damp basements).
Animals, especially cats, can be highly allergenic and in sensitized individuals can cause significant symptoms. Cats and dogs are the most common pets in the United States, with more than one-third to one-half of all homes housing at least one cat or dog.64 Birds, rabbits, hamsters, guinea pigs, rats, and mice are some other potentially allergenic pets. The major allergens of the cat and the dog are found in their saliva and sebaceous glands. The cat allergen can remain a potential source of allergy months after the removal of the cat, because of its light, sticky qualities.
Outdoors, inhalation of the emanations of moths, locusts, beetles, and flies may cause allergic symptoms. Residents of the area around western Lake Erie may experience allergic symptoms caused by the mayfly.76 Finally, the cockroach is potentially allergenic and is frequently encountered in heavily infested, crowded, or multifamily dwellings.
The main functions of the nose—to warm, humidify, and filter air—are possible because of turbulent airflow resulting from increased surface area provided by the three turbinates (superior, middle, and inferior) on each side. The nose’s functions are mainly controlled by the underlying neurovascular system. Blood supply to the nose is via the ophthalmic (branch of the internal carotid) and internal maxillary (branch of the external carotid) arteries. Neural innervations include the sensory (via the trigeminal nerve, which is responsible for the sneezing reflex) and autonomic (parasympathetic and sympathetic) nervous systems. Nasal congestion is proportionally related to the amount of blood pooling in the cavernous sinusoids (located within the turbinates) and to the degree of mucosal edema. Sinusoid filling and emptying are controlled by the autonomic nervous system. Vasodilatory parasympathetic stimulation allows the sinusoid reservoir to fill via opening and closing of capillary and postcapillary venule sphincters, respectively. Conversely, sympathetic stimulation contracts the capillary sphincter and relaxes the postcapillary venule sphincter, allowing the reservoir to empty.
In most people, cyclic swelling and shrinking of the turbinates between the two sides of the nose is inherent. This nasal cycle, which is approximately 1 to 4 hours in length, results from alternating sympathetic discharge and is responsible for the sensation of alternating unilateral nasal blockage experienced by allergic rhinitis sufferers.22
Another major function of the nose is olfaction. The olfactory area is located at the roof of the nasal cavity above the middle turbinate. Significant turbinate edema can lead to poor ventilation of this area and associated hyposmia, which is common among allergic rhinitis sufferers.
A thorough, careful history is crucial in evaluation of allergic rhinitis and is often helpful in determining whether or not an individual is allergic. Allergy testing is used to confirm the underlying clinical suspicion. Symptoms of allergic rhinitis can range from intermittently mild to incapacitating, such as during peak pollen season. The hallmark of allergic rhinitis is temporal correlation of symptoms with allergen exposure.46 The most common symptoms of allergic rhinitis—sneezing, nasal congestion, rhinorrhea, and pruritus of the nose and eyes—are nonspecific. Itching and sneezing are the most distinctive complaints associated with allergic rhinitis,47 whereas nasal congestion seems to be more prominent in perennial rhinitis than in seasonal rhinitis. In some individuals, ocular symptoms predominate over nasal symptoms. Allergic rhinitis sufferers often experience the priming effect (an increase in sensitivity to allergens after repeated exposure) and hyperresponsiveness to nonallergenic environmental stimuli, such as tobacco smoke, strong odors, pollutants, and weather changes.11
Since the time intervals of pollination are predictable in a given season, the timing of symptoms is often helpful in identifying the responsible pollen(s). For example, in the Midwest, ragweed sufferers characteristically start experiencing symptoms in mid-August. Conversely, because any number of allergens may cause symptoms in individuals with perennial rhinitis, determining the specific responsible allergen(s) can be difficult. Other conditions of the upper respiratory tract may mimic allergic rhinitis and must be considered. Complications of allergic rhinitis include sinusitis, otitis media with effusion, and asthma. Additionally, numerous studies have shown that allergic rhinitis may significantly affect quality of life, with effects such as sleep loss, fatigue, poor concentration, reduced productivity, and irritability.28 Although a decline in their quality of life may seem like an obvious clue to the severity of the disease, patients may not be aware of this decline if they have been living with their condition for years and have become accustomed to it.71
As is true for the symptoms described by the patient, many of the signs noted on physical examination are not exclusive to allergic rhinitis. Classically, the nasal mucosa is pale blue and edematous, but this color change is noted in only 60% of sufferers, and many individuals have erythematous mucosa.15 In children, the “allergic salute” (upward nasal rubbing) and “allergic shiners” (dark, puffy circles under the eyes) may be present. Other notable signs include septal deviation, polyps, and an obvious foreign body. If congestion is profound, use of a topical decongestant such as oxymetazoline (Afrin) may improve visualization.
Because of the temporal correlation of symptoms with a particular season, diagnosis of seasonal allergic rhinitis can often be made clinically without the need for testing. However, given the ambiguity of various allergen exposures in perennial rhinitis, allergy testing is generally recommended. Allergy testing may be performed either by skin testing or by the radioallergosorbent test (RAST). In skin testing, which is widely accepted and more sensitive,30 minute quantities of specific allergens are introduced under the skin, and a positive response depends on allergen-specific release of histamine. In the RAST, evidence of allergen-specific IgE is determined using the patient’s serum. Given its lesser sensitivity, greater cost, and longer turnaround time for results, RAST is typically used in special circumstances only, such as for patients with severe eczema or dermatographism, in whom skin testing might be difficult to interpret.
Given the significant and overlapping symptoms of various rhinitis conditions, the differential diagnosis of rhinitis must be considered during the initial evaluation (Box 62-1). Rhinitis can be classified as acute or chronic. The most common cause of acute rhinitis is a viral infection, and allergic rhinitis may be confused with viral rhinitis. However, unlike the symptoms of allergic rhinitis, those of viral rhinitis usually do not persist longer than 2 weeks unless superseding sinusitis develops. A foreign body or trauma also can cause acute rhinitis. Unilateral symptoms are the hallmark of foreign body obstruction.
BOX 62-1 Differential Diagnosis of Rhinitis
The differential diagnosis of chronic nonallergic rhinitis is broad. Nonallergic rhinitis with eosinophilia syndrome (NARES) is characterized by (1) symptoms similar to allergic rhinitis, (2) eosinophilia on nasal smear, and (3) a negative skin test.27 Chronic sinusitis, which can occur as a complication of allergic rhinitis, commonly causes nasal congestion, sinus pressure, postnasal drip, cough, and diminished senses of smell and taste. Symptoms of chronic sinusitis, unlike those of acute sinusitis, are subtle and may require radiologic evaluation, preferably computed tomography. Systemic diseases, such as vasculitis and cystic fibrosis, may cause chronic rhinitis. Rhinitis medicamentosa, which usually results from overuse of topical α-adrenergic vasoconstrictors (e.g., oxymetazoline), is associated with profound nasal congestion caused by rebound effects on withdrawal of the decongestant, usually after 5 to 7 days of topical use. Medications that have been implicated in chronic rhinitis include nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors, and β-blockers.
Mechanical and anatomic abnormalities should always be sought on physical examination. Nasal polyps have a pearly, smooth, peeled grape-like appearance and are often bilateral. Nasal polyps may be associated with chronic sinusitis, asthma, and aspirin sensitivity.63 Unilateral symptoms should always heighten suspicion for a foreign body or tumor. Some degree of septal deviation may be found in most people. Therefore, unless symptoms are severe, treatment is unnecessary. In children, adenoid hypertrophy must be considered.
Symptoms of gustatory rhinitis are caused by a cholinergic response that occurs after such stimuli as eating, running, and exposure to cold air. Atrophic rhinitis is a rare condition that manifests in older adults as a thick, bilateral, odorous discharge with little nasal congestion.21 Rhinitis of pregnancy should be considered in the pregnant woman with congestion, especially if there is no previous history of rhinitis. Although rare, cerebrospinal fluid (CSF) leak must be considered in anyone with clear rhinorrhea and a history of central nervous system trauma. Testing for the presence of glucose in the nasal mucus is helpful in making the diagnosis. The diagnostic test of choice to detect CSF leak is an assay for a β-2 transferrin level in the nasal mucus.65
Often a diagnosis of exclusion, vasomotor (idiopathic) rhinitis is a common cause of nonallergic rhinitis in adults. Although the term implies a cause relating to vascular or neurologic dysfunction, the mechanism of vasomotor rhinitis is poorly understood. The symptoms of vasomotor rhinitis are frequently obstructive rather than secretory. Therefore nasal congestion and sinus pressure predominate over sneezing and rhinorrhea.39 Individuals with vasomotor rhinitis typically experience perennial symptoms that may be triggered by changes in weather, spicy foods, and irritants, such as smoke, strong scents, and chemicals.