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MD Consult: Books: Goldman: Cecil Medicine: Chapter 272 – ALLERGIC RHINITIS AND SINUSITIS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 272 – ALLERGIC RHINITIS AND SINUSITIS

 

Larry Borish

 

Definition

 

Allergic rhinitis (AR) refers to the nasal and ocular symptoms that occur as a result of the development of an inflammatory hypersensi-tivity reaction to aeroallergens deposited on the nasal mucosa and conjunctiva.

Epidemiology

 

AR, the most common chronic disease in the United States, affects between 9 and 24% of adults and up to 42% of children. Each year, nearly 80 million people in the United States experience 7 or more days of nasal or ocular symptoms as a result of AR. Although it is not a severe disorder, the socioeconomic costs of AR are substantial. AR is one of the chief reasons for visiting a primary care physician, it adversely affects work productivity and school performance, and it limits socialization. Its impact also reflects the involvement of AR with a variety of comorbid conditions, including asthma ( Chapter 87 ), chronic sinusitis, nasal polyposis, secretory otitis media, and sleep disorders. Adequately addressing AR requires a thorough understanding of its pathophysiology, its relation to these comorbid conditions, and the effects of various therapeutic options on the pathophysiology of AR and its associated comorbidities.

Pathobiology

 

Airborne Allergens

 

Allergic respiratory diseases result from a hypersensitivity immune reaction to airborne allergens. These include the seasonal pollens and molds that are responsible for seasonal AR (SAR) and the indoor allergens, such as house dust mites and animal proteins, that are responsible for perennial AR (PAR) ( Table 272-1 ).
TABLE 272-1   — ALLERGENS CAUSING ALLERGIC RHINITIS

Seasonal Allergens
Common Name Season
TREES
Birch March–May
Cottonwood April–May
Elm February–May
Cedars March–May
Oak May–June
Maple March–May
GRASSES
Kentucky blue mid-May–June
Timothy mid-May–June
Orchard mid-May–June
Sweet vernal mid-May–June
Fescue mid-May–June
WEEDS
Ragweed August–September
Kochia July–September
Russian thistle July–September
Sage July–September
Marsh elder July–September
English plantain July–September
OUTDOOR MOLDS
Alternaria Spring–fall
Cladosporium Spring–fall
Perennial Allergens
HOUSEHOLD ALLERGENS
Cockroaches (German and American)
Dust mites: Dermatophagoides farinae, Dermatophagoides pteronyssinus, Blomia tropicalis
Other insects (spiders, ladybugs)
ANIMALS
Cats
Other pets (guinea pigs, ferrets, hamsters, horses)
Rodents
Dogs
? Chicken feathers
INDOOR MOLDS
Aspergillus
Cladosporium
Penicillium

In any area, the specific pollens that are likely to cause symptoms can be predicted from the number of days that a particular pollen is airborne in large numbers. All these pollens utilize a windborne mechanism to produce fertilization. Insect-borne pollens, specifically those produced by flowers, are not significantly airborne and therefore are not inhaled in sufficient concentrations to generate immune responses. In the United States, grass pollens (May to June) and ragweed (mid-August to October) are the most important causes of SAR. Tree pollens vary locally but typically start in late February and continue through April. The major trees implicated in allergy include birch in the North, oak in the mid-Atlantic region, live oak in the South, and mountain cedar in the Southwest. In addition to pollens, outdoor molds, particularly Alternaria and Cladosporium can produce symptoms. These molds have variable sporing seasons, depending on the weather, and high levels of airborne fungi are common at any time between March and October.

PAR may continue year round, but the term is applied to any rhinitis that does not have a clearly defined seasonal association. The most common causes include the following: (1) indoor fungi, which are related to periods of high indoor humidity and the availability of sites to grow; (2) animal danders, the most important being cats, but rodents (mice, rats, guinea pigs, ferrets, hamsters), rabbits, dogs, and birds may also be significant; (3) dust mites of the genus Dermatophagoides that grow in carpets, bedding, pillows, sofas, and so forth and that are semiseasonal, with maximum levels from August to December; and (4) other insects (the best studied is the cockroach, but gypsy moths, crickets, ladybugs, spiders, and beetles may also be locally important). Dust mites and cats produce the most important indoor allergens. Dust mites grow well only with a relative humidity higher than 55%. Dust mite allergy is therefore of major importance in the southeastern United States and also on the West Coast, Hawaii, and the Gulf Coast. It is probably relevant in all areas with more than 6 humid months in the year.

Immunoglobulin E/Mast Cell/Basophil Activation

 

Traditionally, AR is viewed as caused by triggering mast cell degranulation resulting from cross-linking of surface-bound immunoglobulin E (IgE) molecules by the aeroallergen. As with all antibody-mediated immune responses, the initial exposure to the antigen results in B-lymphocyte secretion of low-affinity IgM antibodies. Subsequent exposure to the allergen, in genetically predisposed subjects, leads to a secondary immune response characterized by the isotype switch to IgE. The resulting release of IgE antibodies into the circulation, however, does not cause allergic symptoms. It is only after the binding of these IgE antibodies to their high-affinity receptors on basophils and mast cells that symptoms can develop with subsequent allergen exposures. It takes cross-linking of approximately 300 IgE receptors/cell to stimulate degranulation. As such, it often requires several allergy seasons before sufficient numbers of allergen-specific IgE molecules are present on the mast cell surface to drive degranulation. The development of symptomatic AR is therefore a protracted process, generally requiring at least three or four exposures. As a result, SAR generally is not observed in infants until they are approximately 4 years of age. Similarly, in adults, symptomatic responses to local allergens may not develop until approximately 4 years after moving to the relevant region. PAR, however, can develop much faster.

Within minutes of allergen exposure, IgE-sensitized mast cells degranulate and release preformed and newly synthesized mediators, including histamine, proteases (tryptase and chymase), cysteinyl leukotrienes, prostaglandins, and cytokines. Some of these mediators produce the characteristic early-phase symptoms of AR, namely, sneezing, pruritus, rhinorrhea, and, to some extent, congestion, whereas other mediators stimulate infiltration of the nasal mucosa with inflammatory cells, including basophils, eosinophils, neutrophils, additional mast cells, and mononuclear cells. This infiltration of inflammatory cells and their subsequent release of a secondary wave of mediators sustain the inflammatory reaction with the continued recruitment of inflammatory cells and produce the late-phase response of AR. This slowly developing inflammatory response is primarily characterized by nasal congestion. The inflammation that develops over the course of an allergy season is associated with an approximately 10-fold increase in the numbers of mast cells present in nasal epithelial and submucosal tissue ( Fig. 272-1C ). This reflects the migration of preexisting mast cells into the epithelium and the differentiation and influx of newly synthesized mast cells into the nasal mucosa under the influence of cytokine growth factors. In the course of chronic allergen stimulation, these mast cells also display increased priming that reflects increases in numbers of IgE receptors and surface-bound IgE, as well as enhancement of signal transduction pathways. As the allergen season progresses, less and less allergen is required to trigger mast cell degranulation. In addition, as a result of priming, perennial allergens that are not sufficient by themselves to trigger an allergic reaction may exacerbate symptoms present during an allergy season.

 

 

FIGURE 272-1  Findings in allergy. During an allergy season when birch pollen was elevated (A), associated nasal symptom scores gradually increased (B) and correlated significantly with the logarithm of the pollen count (r = 0.68; P < .01). A significant increase of the number of mast cells in the imprint area (C) and percentage of eosinophils in nasal lavage (D) also occurred during the allergy season compared with preseason values.  (From Pipkorn U, Karlsson G, Enerback L: The cellular response of the human allergic mucosa to natural allergen exposure. J Allergy Clin Immunol 1988;82:1046-1054.)

Although mast cells play an important role during the initial AR response, they do not play as substantive a role in sustaining this response. Histamine secretion occurs during both early and late phases after allergen exposure, whereas prostaglandin D2 increases only during the early phase. Because mast cells synthesize prostaglandin D2, the absence of this mediator during the late phase indicates that mast cells are not responsible for the late-phase increase in histamine. Basophils release histamine, but, in contrast to mast cells, they do not produce prostaglandin D2 and presumably are the source of this later histamine release.

Antigen-Presenting Cell/Helper T-Lymphocyte Activation

 

In addition to their interaction with mast cells, allergens also behave like any other foreign antigen and are processed and presented by antigen-presenting cells to helper T (TH) lymphocytes. Activation of these antigen-presenting cells, including mononuclear phagocytic cells, B lymphocytes, and especially dendritic cells, is an important source of cytokines, especially those associated with innate immunity such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α). With the development of allergic inflammation, one notes an increased presence of B cells expressing allergen-specific surface immunoglobulin and dendritic cells expressing IgE bound to their high-affinity IgE receptor. These antibodies can function as allergen receptors that “capture” allergen and increase these cells’ effectiveness in antigen processing. The newly activated T lymphocytes tend to resemble TH2 cells, characterized by their production of IL-4, IL-5, IL-9, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are also major components of the inflammatory response in AR and contribute to the increased production, recruitment, and activation of eosinophils, mast cells, and basophils. A milieu rich in IL-4 and IL-13 drives the IgE isotype switch and contributes to the further production of allergen-specific IgE and de novo IgE production to bystander antigens.

As a result of these inflammatory processes, over the course of allergen exposure, rhinitis evolves to become more dependent on mediators associated with the infiltration of cells such as eosinophils, basophils, neutrophils, mononuclear cells, and TH lymphocytes, as well as the increasingly primed mast cells. The symptoms of acute rhinitis such as sneezing, itching, and rhinorrhea largely reflect vasoactive mediator release, especially histamine. As SAR or PAR persists, however, these infiltrating cells with their continued production of cytokines and other inflammatory mediators lead to the mucus hypersecretion, tissue edema, goblet cell hyperplasia, and tissue damage that become the primary sources of allergy patients’ symptoms. Because the role of histamine diminishes as AR progresses, as discussed later, antihistamines become less effective.

Eosinophils represent an important component of the inflammation that develops in PAR and affects the progression of SAR. Eosinophils release a wide variety of proinflammatory mediators, including cysteinyl leukotrienes (leukotrienes C4, D4, and E4), eosinophil cationic protein, eosinophil peroxidase, major basic protein, IL-3, IL-5, GM-CSF, and platelet-activating factor. Eosinophil-derived mediators are major components of the chronic allergic response and produce many of the symptoms of AR, especially nasal congestion. The natural history of SAR is for symptoms to worsen inexorably over several weeks in the presence of ongoing allergen exposure. As shown in Figure 272-1B , symptoms often do not peak until well after the peak in pollen counts (see Fig. 272-1A ), and then they persist after pollen counts have declined dramatically. These observations reflect the time frame of the onset of nasal inflammation and tissue damage. The influx of eosinophils into the nasal mucosa (see Fig. 272-1D ) correlates closely with the development and progression of symptoms. In summary, the natural history of AR represents an evolution from an acute, primarily mast cell–mediated process that is responsive to antihistamines to a chronic inflammatory process that is primarily eosinophil mediated and is much less responsive to antihistamines.

Clinical Manifestations

 

The diagnosis of AR is based on a history of sneezing, which is often paroxysmal, rhinorrhea with clear watery secretions, nasal congestion, and itching in the nares and palate. These symptoms are generally associated with allergic conjunctivitis manifested by ocular itching, lacrimation, and conjunctival injection. Severe conjunctivitis is less common in PAR, in contrast to SAR. The best explanation for this difference is that pollen grains affect the eyes when they are blown into them. Indoor allergens are less likely to be blown into the eyes because the air is relatively still. Indoor aeroallergens are drawn into the nose by breathing.

What historically has been less well appreciated is that AR is a systemic disease associated with circulating activated T lymphocytes and mononuclear phagocytic cells. The activation of these cells is demonstrated by their production of cytokines associated with innate immunity such as IL-1, TNF-α, and IL-6. These cytokines are responsible for the lethargy, fatigue, arthralgias, and myalgias that frequently accompany AR. AR is also associated with cognitive impairment in schoolchildren and adults. These systemic symptoms, which are often the chief complaints of allergy sufferers, contribute to the complaints of diminished quality of life and are often severe enough to make normal activities difficult, including work or school. Although fever is not regarded as a feature of AR, it is intriguing that the lay terminology for this condition is hay fever, a designation reflecting the pronounced flulike nature of this disease.

Diagnosis

 

AR is primarily a clinical diagnosis based on symptoms and exposure history. It is a complex genetic disorder, and affected patients generally give a positive family history. Physical examination reveals the nasal mucosa to be pale, cyanotic, and swollen with clear secretions. In children, a transverse nasal crease, a high arched palate, mouth breathing, and dental malocclusion are often observed. Periorbital venous dilation produces “allergic shiners.” Nasal smears (Hansel stains) of nasal secretions are seldom required, but when performed they typically reveal eosinophils.

The diagnosis of AR is confirmed by demonstration of specific IgE antibodies reactive to the relevant pollen through either positive allergy skin tests or IgE immunoassays. In addition to confirming the diagnosis of AR, identification of specific triggering allergens is essential for recommending appropriate environmental controls specific to the causative allergen. Prick skin testing is safe, specific, rapid, and the diagnostic test of choice for identifying relevant allergens. Intradermal testing is rarely associated with potentially life-threatening systemic reactions. A positive intradermal test in the presence of a negative prick skin test is often a false-positive result and requires careful interpretation. If a referral for prick skin testing is not available or if the test cannot be performed (e.g., patients with eczema or dermatographism, patients using antihistamines, antiemetics, antipsychotic agents, or young children), in vitro testing (IgE immunoassays) can provide useful data. These tests are less sensitive than skin testing; however, positive IgE immunoassays correlate with symptoms on natural exposure, they establish the diagnosis of AR, and they can form the basis for environmental therapy and therefore should be extensively used by primary care physicians who manage patients with AR. However, a negative IgE immunoassay with a strong clinical suspicion should suggest the need for referral.

Differential Diagnosis

 

Other causes of rhinitis are shown in Table 272-2 , and the approach to the patient with sneezing and rhinorrhea is displayed in Figure 272-2 . Viral rhinitis may be difficult to distinguish from SAR. Viral rhinitis is not associated with release of mast cell mediators. The main mediators present in nasal secretions from patients with the common cold are kinins, whereas leukotrienes and prostaglandins are generally less prevalent. The presence of these different mediators is in keeping with the observation that most allergic patients can distinguish the symptoms of the common cold from those caused by allergen exposure. Pruritus, paroxysmal sneezing, and clear secretions help to distinguish SAR from viral rhinitis, along with the distinct recurrent seasonal nature of SAR. Viral rhinitis produces thicker, purulent secretions, with neutrophils present on the nasal smear. Conjunctival symptoms are less pronounced, and on physical examination the nasal mucosa is erythematous and swollen. Hormonal influences that may produce chronic nasal congestion and rhinorrhea include hypothyroidism, birth control pill use, pregnancy, and menopause. Abuse of topical nasal decongestants (e.g., oxymetazoline) with chronic reflex vasodilatation has historically been the most common cause of rhinitis medicamentosa; however, cocaine abuse may have surpassed decongestants as the most common cause of this condition. Chronic unilateral nasal blockage suggests an anatomic defect, typically a deviated or fractured septum, but such blockage can also result from polyps, tumors, and foreign bodies. This history necessitates evaluation with computed tomographic scanning of the nose and sinuses and possibly rhinoscopy. Nasal septum deviation hardly ever causes bilateral nasal congestion, and surgical therapy has little role in the treatment of rhinitis that is producing symptomatic congestion.
TABLE 272-2   — DIFFERENTIAL DIAGNOSIS OF RHINITIS

ALLERGIC
Seasonal allergic rhinitis (SAR)
Perennial allergic rhinitis (PAR)
INFLAMMATORY
Infectious rhinitis (viral)
Nonallergic rhinitis with eosinophilia syndrome (NARES)
Chronic sinusitis with or without nasal polyposis
HORMONAL
Pregnancy, oral contraceptive use, perimenopause
Hypothyroidism
Hyperthyroidism
RHINITIS MEDICAMENTOSA
Topical decongestants
Antihypertensives
Antidepressants
Cocaine
VASOMOTOR
Irritant induced (pollution, cigarette smoke)
Cold air induced
Gustatory (food induced)
ANATOMIC
Nasal septal deviation
Tumor, neoplasm
Foreign body
Cerebrospinal fluid leak
Atrophic (postsurgical or trauma)

 

 

FIGURE 272-2  Approach to the patient with rhinitis symptoms. CT = computed tomography; HA = headache; IgE = immunoglobulin E; NARES = nonallergic rhinitis with eosinophilia syndrome; PAR = perennial allergic rhinitis; SAR = seasonal allergic rhinitis.

An abnormal neurogenic response to irritants (e.g., cold air, pollutants, cigarette smoke, strong odors, alcohol, and foods) is the predominant feature of vasomotor rhinitis. This disorder is characterized by nasal autonomic nerve dysfunction. Patients with this vasomotor rhinitis typically have chronic nasal congestion and posterior pharyngeal drainage, but they lack the sneezing, rhinorrhea, pruritus, conjunctivitis, and systemic complaints typical of patients with AR. Patients with vasomotor rhinitis have negative allergen skin tests and an absence of eosinophils in their nasal mucus. Topical antihistamines (nasal azelastine) are often effective in vasomotor rhinitis. Patients with this condition occasionally respond to therapy with topical corticosteroids or atropine (nasal ipratropium).

Chronic sinusitis with or without nasal polyposis produces a spectrum of symptoms that includes rhinorrhea, mucopurulent posterior pharyngeal drainage, and nasal congestion that can be confounded with PAR. A computed tomographic scan is often required to establish the diagnosis of sinusitis. Atrophic rhinitis is characterized by atrophy of the nasal epithelium and is associated with complaints of nasal congestion and a perceived bad odor. It is observed in elderly patients, but the most common cause is devascularization secondary to nasal surgery or trauma. Finally, a nonallergic nasal disease characterized by prominent eosinophilic inflammation has been described and termed non-AR with eosinophilia syndrome (or NARES). On further analysis, many of these patients prove to have chronic sinusitis and nasal polyps. Patients with NARES present with symptoms similar to those of vasomotor rhinitis. NARES is diagnosed by performing a nasal smear (Hansel stain) for eosinophils. In contrast to vasomotor rhinitis, NARES is more often responsive to intranasal cromolyn and corticosteroids.

Systemic Manifestations of Allergic Rhinitis

 

Allergic inflammation associated with AR can lead to obstruction of the sinus ostia and is an important cause of acute (bacterial) sinusitis. More important is the association of AR with chronic sinusitis. Chronic sinusitis represents many disease processes including those caused by chronic bacterial infections, cystic fibrosis, immotile cilia syndrome, immune deficiencies, nonspecific inflammation, hypersensitivity to colonized fungi, and a manifestation termed chronic hyperplastic eosinophilic sinusitis (CHES). Approximately half of all patients with chronic sinusitis have CHES, and this discussion focuses on the underlying allergic mechanisms.

CHES, which generally occurs in association with nasal polyposis, is an inflammatory disorder characterized by the accumulation of eosinophils, fibroblasts, mast cells, goblet cells, and TH2-like lymphocytes. The prominent accumulation of eosinophils, however, is the diagnostic feature of this condition ( Fig. 272-3 ). The sinus tissue is infiltrated with a marked increase in cells, including lymphocytes, fibroblasts, and eosinophils, which are expressing cytokines responsible for eosinophilopoiesis (IL-5), survival (IL-3, IL-5, and GM-CSF), recruitment (CCL11 [eotaxin]), and activation (CCL11, CCL5 [RANTES], IL-3, IL-4, IL-5, GM-CSF, and TNF-α). Both sensitivity to multiple allergens and, more specifically, sensitivity to perennial allergens, such as dust mites, increase the risk of developing CHES. More than 50% of individuals with PAR have abnormal sinus radiographs. Allergens are unlikely to gain access to the sinus cavities in healthy subjects (they are not inhaled into the sinuses with breathing, and diffusion is not efficient), and they are even less likely to do so in the presence of the occlusions of the sinus openings that are characteristic of sinusitis. Studies performed with insufflation of radiolabeled ragweed particles confirm the inability of these pollens to enter the sinuses. The link between AR and sinusitis is thought to involve a systemic inflammatory process ( Fig. 272-4 ).

 

 

FIGURE 272-3  Immunohistochemical analysis of a sinus biopsy from a patient with sinusitis and chronic allergic rhinitis. Eosinophils were labeled with an antibody to eosinophil cationic protein and were localized as aggregates within and beneath the epithelium. (Original magnification × 400.)  (From Demoly P, Crampette L, Mondain M, et al: Assessment of inflammation in noninfectious chronic maxillary sinusitis. J Allergy Clin Immunol 1994;94:95-108).

 

 

FIGURE 272-4  In sensitized subjects, allergen exposure activates immune cells including helper T (TH) lymphocytes, dendritic cells, mononuclear phagocytic cells, mast cells, and others both within the nares and in nasal-associated lymphatic tissues. These cells may also include locally produced CD34+ interleukin-5 receptor-positive (IL-5R+) eosinophil/basophil (Eo/B) progenitors. These newly activated TH lymphocytes will have the phenotype of TH2-like cells characterized by their production of IL-3, IL-4, IL-5, IL-9, IL-13, CCL11 (eotaxin), and granulocyte-monocyte colony-stimulating factor (GM-CSF). Some of these TH cells migrate to the bone marrow, where they stimulate the bone marrow to produce inflammatory cells including basophils, mast cells, and—most importantly—eosinophils. Ultimately, these newly generated inflammatory cells enter the circulatory system from which they are selectively recruited back to the nose, but also to the sinuses (and lungs), thus exacerbating inflammation. This selective recruitment of inflammatory cells into the sinuses and lungs occurs only in individuals with preexisting chronic hyperplastic eosinophilic sinusitis and asthma in whom specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), and chemoattractants, such as CCL11, already exist. VLA-4 = α4B1 integrin; very late antigen-4.  (From Borish L: Allergic rhinitis: Systemic inflammation and implications for management. J Allergy Clin Immunol 2003;112:1021-1032.)

AR is not just a localized inflammatory disorder of the nasal mucosa, but rather it is associated with systemic inflammation; consequently, it is often seen with other inflammatory conditions, such as asthma ( Chapter 87 ), secretory otitis media, and CHES. For example, in patients with SAR who also have asthma, nasal allergen provocation, done such that the allergen does not gain access to the lungs, leads to increased adhesion molecule expression, eosinophil infiltration, and increased bronchial hyperreactivity. As illustrated in Figure 272-4 , in sensitized subjects, allergen exposure activates immune cells, including TH lymphocytes, dendritic cells, mononuclear cells, mast cells, and others both within the nares and in nasal-associated lymphatic tissues. These cells also include locally produced eosinophil precursors. Some of these TH cells migrate to the bone marrow, where they stimulate the bone marrow to produce inflammatory cells, including basophils, eosinophils, and mast cell precursors. Thus, allergen challenges increase the bone marrow concentrations of both cytokines and eosinophil/basophil progenitor cells. Ultimately, these newly generated inflammatory cells enter the circulatory system, from which they are selectively recruited to the sinuses in CHES (and lungs in asthma). This selective recruitment of inflammatory cells into the sinuses occurs only in individuals with preexisting CHES in whom specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), and chemoattractants, such as CCL11 (eotaxin), are already present. Persons without CHES do not have these addressins in their sinuses and thus do not have the machinery in place to recruit inflammatory cells in response to their AR. This model explains the absence of CHES in approximately half of AR sufferers, but it does not explain the precipitating event that initiates CHES and allows AR to perpetuate the sinus inflammation once it is established.

In support of these concepts, nasal allergen challenges in sensitive individuals produce radiographic changes within the maxillary sinuses, including edema and opacification. Similarly, during seasonal exacerbations of AR, worsening of CHES can be demonstrated. Nasal allergen challenges in allergic individuals produce significant increases in eosinophils, eosinophil cationic protein, histamine, and albumin not only in the nose but also in the maxillary sinus. In one study, sinus lavage fluid from both maxillary sinuses was collected and analyzed after a nasal allergen challenge was performed in only one side of the nose. Both albumin levels and eosinophil counts were significantly increased in these specimens, with no significant differences detected in specimens obtained from the ipsilateral and contralateral maxillary sinuses. Similar systemic mechanisms could produce an interaction between AR and secretory otitis media or asthma. It is not known whether treating AR can lessen severity of CHES, but the observation that nasal-directed therapies can attenuate bronchial inflammation and symptoms of asthma suggest that such a linkage is plausible.

Prevention

 

Avoidance and Environmental Control

 

When feasible, avoidance or elimination of the source of allergen is the treatment of choice for patients with AR. Avoidance studies in AR are limited (as opposed to asthma), and the amount of allergen reduction needed to reduce symptoms effectively is unknown. Avoidance studies in asthma ( Chapter 87 ) provide compelling evidence for beneficial effects on bronchial hyperreactivity, symptom severity, and need for β-agonist rescue therapy. Dust mite avoidance involves four principles: (1) remove reservoirs for mite growth (i.e., cover mattresses and pillows with allergen-impermeable covers and remove fitted carpets and upholstered furniture from the bedroom); (2) keep the relative humidity lower than 50%; (3) wash bedding in a hot cycle (130° F) because cool cycle washing of bedding does not kill mites, nor does the dryer; (4) wear a simple mask at times when dust is being disturbed and for 10 minutes afterward, to allow large particles to settle. Many of the measures suggested for mites are also helpful for fungi, especially dehumidification. Windows, shower curtains, and indoor plants are important sites for fungal growth and can be treated with mild fungicides (dilute household bleach).

In some houses, and particularly urban apartment blocks, large numbers of cockroaches are present, and IgE sensitivity to cockroach allergen extracts is common. Although it may be difficult to kill cockroaches in an apartment, it is usually possible to keep a house clear of cockroaches by using chemical sprays and traps, for example. Care must be taken when using chemical sprays because they may prove to be an irritant to asthmatic patients. Air conditioning with closed windows is useful for reducing seasonal allergens, and the dehumidification provided by air conditioning also mitigates mite and indoor mold load.

Pets, especially cats, are the most preventable source of allergic diseases and should be eliminated from the home of the patient with AR. Animal dander accumulates in houses over a prolonged period and takes many months to eliminate after the cat, dog, or pet rodent is removed. Although it is difficult to persuade patients to get rid of animals, it may be possible to move the pet out into the garage or restrict the range of pets in the house. Dogs kept outside, washed regularly, and allowed into the house only occasionally do not appear to be an important cause of sensitization or symptoms. Cat allergy is a much more serious problem because a single cat deposits a huge concentration of allergens. Cat owners themselves can, in turn, deposit sufficient concentrations of allergen in schoolrooms and other environments to induce symptoms in their allergic colleagues. The dominant rodent allergen is a urinary protein, and, like cats, rodents can deposit large quantities of allergen in patients’ houses.

Treatment

 

 

 

 

Although avoidance interventions significantly reduce allergen levels, as single interventions they often fail to produce clinically significant improvements. [1] [2] As a result, pharmacotherapy is frequently required.Evidence-Based Treatments

 

Antihistamines

 

Antihistamines are the oldest drugs used in the treatment of AR and are considered first-line therapy. Antihistamines compete with histamine for the H1-receptor sites that contribute to sneezing, itching, rhinorrhea, and conjunctivitis. Oral antihistamines therefore ameliorate these symptoms of AR but in general do not improve nasal congestion. They also inhibit mast cell activation as manifested by diminished histamine, cysteinyl leukotrienes, and mast cell tryptase secretion. First-generation antihistamines cross the blood-brain barrier and have significant sedative and anticholinergic effects. In addition to causing sleepiness, they interfere with school, work, driving, or use of machinery. Whereas only 10 to 15% of treated patients complain of sedation, virtually all subjects demonstrate decreased motor skills, diminished driving ability, and slower electroencephalographic response times when they are given first-generation antihistamines (e.g., chlorpheniramine, diphenhydramine, and clemastine). Therefore, the use of these drugs is no longer recommended. Second-generation antihistamines have a longer duration of action, do not cross the blood-brain barrier, and are nonsedating. These agents include fexofenadine, descarboxyloratadine, and loratadine. Although it is less sedating than its parent compound hydroxyzine, cetirizine may occasionally produce sedation. The intranasal antihistamine azelastine may not produce a significantly more rapid onset of action than currently available oral antihistamines, but in contrast to oral antihistamines, it has decongestant efficacy and is often useful in nonallergic forms of rhinitis. No studies have convincingly demonstrated the superiority of one oral antihistamine over another.

As discussed earlier, the role of histamine diminishes as AR progresses over the course of an allergy season or with PAR, and this consequently makes antihistamines less effective. This progression is responsible for the diminished efficacy of antihistamines observed over the course of an allergy season. Antihistamines are quite effective for acute allergic reactions, which are mediated prominently by mast cell–derived histamine, and as such are most beneficial in patients with intermittent allergen exposures such as occasional outdoor exposure during pollen season. In patients with continuous allergen exposures, however, such as PAR caused by indoor allergens or after several days of continuous exposure to seasonal allergens, these drugs often prove to be little better than placebo. [3] [4]

Decongestants

 

Decongestants such as pseudoephedrine treat nasal stuffiness but are mild stimulants. These drugs are usually used in combination with antihistamines to control the full spectrum of symptoms of AR. Antihistamines and decongestants alone generally do not provide satisfactory relief in patients with moderate to severe AR.

Leukotriene Modifiers

 

Leukotriene modifiers (zileuton, zafirlukast, montelukast) have confirmed efficacy in AR comparable to that of antihistamines.[4] This efficacy reflects the presence and importance of these pro-inflammatory vasoactive mediators to AR. Zafirlukast significantly reduced sneezing, rhinorrhea, and—in contrast to antihistamines—nasal congestion in patients with SAR.[5] Similarly, montelukast significantly improved nasal and ocular symptoms as well as quality of life in patients with SAR and PAR.[4] No studies have been performed to determine whether, in contrast to antihistamines, leukotriene modifiers may have additive effects with intranasal corticosteroids in patients with refractory AR.

Nasal Cromolyn

 

Nasal cromolyn stabilizes mast cells and mediates additional anti-inflammatory activities toward macrophages and T lymphocytes. Although not as effective as intranasal corticosteroids, cromolyn provides relief in patients with mild to moderate symptoms,[6] and it may be effective in combination with corticosteroids in the treatment of refractory symptoms. The value of cromolyn is mitigated by the need for frequent doses (four times/day), a lack of efficacy in approximately 30 to 40% of recipients, and the superior efficacy of intranasal corticosteroids in controlled studies. Cromolyn (one to two sprays in each nostril every 3 to 4 hours) may be especially useful preventively (e.g., immediately before cat exposure or 1 to 2 weeks before the start of the allergen season). Unlike antihistamines, cromolyn controls nasal congestion. Ocular cromolyn has been especially useful in the treatment of allergic conjunctivitis. No significant side effects are associated with its use.

Intranasal Corticosteroids

 

Intranasal corticosteroids (fluticasone [Flonase], triamcinolone [Nasacort], flunisolide [Nasarel], budesonide [Rhinocort], and mometasone [Nasonex]) are the most effective treatments of AR and are considered the treatments of choice for patients with moderate to severe SAR or PAR. [6] [7] Comparative studies of antihistamines and intranasal corticosteroids consistently favor the corticosteroids and show insignificant additive effects when antihistamines are combined with optimal topical corticosteroids.[8] In well-performed placebo-controlled studies, intranasal corticosteroids provided a 50 to 90% reduction in symptoms (compared with 15 to 20% for antihistamines). In contrast to antihistamines, topical corticosteroids reduce nasal congestion, in addition to their relieving itching, rhinorrhea, sneezing, and, in some studies, allergic conjunctivitis. Unfortunately, few studies have addressed the influences of corticosteroids on the systemic effects of AR—including missed work and school, poor productivity, reduced cognition, poor school performance, and fatigue—effects that are often the dominant complaints of patients with AR. Intranasal corticosteroids significantly improve quality of life, a finding reflecting relief from these complaints. Corticosteroid therapy must be given for up to 1 week before it is fully effective, and ideally it should be started before exposures or allergy seasons. However, intranasal corticosteroids begin to produce some clinical improvement in less than 24 hours and possibly as quickly as 6 to 8 hours. Although efficacy is greatest with continuous administration, as-needed intranasal corticosteroids have proven efficacious.

Topical corticosteroid therapy does not inhibit IgE synthesis or mast cell degranulation, traditionally considered to be the two determinants for the development of AR. However, corticosteroids do inhibit T-lymphocyte proliferation, chemokine and cytokine production, arachidonate metabolism, recruitment of eosinophils and basophils, mucus secretion, vascular permeability, and mast cell proliferation. Intranasal corticosteroid use is therefore associated with diminished nasal eosinophilia, mast cell number, and cytokine expression. The efficacy of intranasal corticosteroids emphasizes the importance of these nonhistamine mechanisms to the pathophysiology of AR.

Several intranasal corticosteroid preparations are currently available and differ according to dose, approval age, and propellant ( Table 272-3 ). No studies have demonstrated superior efficacy of any of the various nasal corticosteroid preparations. Clinical experience with asthma ( Chapter 87 ) suggests that patients refractory to one intranasal corticosteroid may be switched to a higher-potency corticosteroid; however, the best evidence is that all these agents are comparably valuable when patients are willing to comply with their use. Choices should primarily be based on patient preference.

No convincing evidence exists for clinically significant systemic absorption and production of systemic side effects from intranasal corticosteroids. Few studies have been conducted regarding the bioavailability of intranasal corticosteroids, but given the hydrophobicity, local metabolism, and lack of absorption from lung tissue associated with these drugs, systemic absorption from the nasal passages is unlikely. Intranasal corticosteroids, even at greater than recommended doses, do not significantly suppress serum or urinary cortisol levels or adrenocorticotropic hormone stimulation tests. Studies have reported a small but statistically significant effect of intranasal corticosteroids on short-term growth velocity in children with PAR. The impact of this finding on ultimate adult height will await further clinical experience, but based on the asthma experience, this is not likely to be shown. Nasal corticosteroids cause minimal topical side effects, including local irritation, dryness, an unpleasant aftertaste, and epistaxis. Adverse side effects may differ based on formulation; aqueous formulations usually produce fewer adverse reactions than aerosols. Nasal biopsy studies do not demonstrate nasal atrophy or decreased ciliary function. Nasal perforation has been reported primarily in the setting of underlying devascularization (previous trauma, surgery, or cocaine abuse).

Immunotherapy

 

The clinical efficacy of immunotherapy for AR caused by grass, ragweed, many other pollens, cat dander, and dust mites has been categorically established in innumerable well-designed controlled studies. Immunotherapy decreases the severity of AR, reduces the need for pharmacotherapy, and significantly improves quality of life. In patients with severe AR and conjunctivitis poorly controlled by antihistamines and intranasal corticosteroids, immunotherapy reduced allergen sensitivity by more than 10-fold, as well as significantly decreasing total symptoms and reducing total antiallergic drug usage. Immunotherapy has also been convincingly established to have efficacy in allergen-exacerbated (extrinsic) asthma ( Chapter 87 ) in studies showing decreased symptoms and the need for β-agonist rescue therapy. Efficacy depends on delivery of the correct antigen, regular injections for 3 to 5 years, and administration of an adequate dose of the allergen (∼10 to 15 μg), a dose significantly higher than those historically utilized.

Immunotherapy is primarily indicated in patients with refractory rhinitis or in patients with unacceptable side effects from standard medications. Because intranasal corticosteroids are not universally effective and do not provide complete relief in all patients, consideration of immunotherapy is necessary. In addition, despite the excellent safety profile of intranasal corticosteroids, many patients remain reluctant to use them. Patients should normally go through at least one full pollen season before the decision is made to consider immunotherapy. An additional indication for immunotherapy is derived from recognition that it is the only treatment that produces long-term immune modulation. Both avoidance and pharmacotherapy are effective only as long as they are sustained. The effects of immunotherapy, in contrast, persist for many years after a 3- to 5-year course of treatment has been discontinued and could be lifelong. [9] [10] A 5-year course of immunotherapy will have cost advantages over lifelong pharmacotherapy. Many patients are attracted to immunotherapy by this potential for long-term immune modulation, remission of symptoms, and the ability to discontinue daily pharmacotherapy.

Immunotherapy is associated with a small risk for fatal anaphylaxis (∼3 fatalities/year in the United States out of ∼2 million people receiving this form of treatment). Because of this risk of anaphylaxis, immunotherapy must be administered only in a facility where resuscitation equipment and trained personnel are available. Asthmatic patients are uniquely at risk for fatal anaphylaxis, and as such immunotherapy should be recommended cautiously to these patients.

TABLE 272-3   — INTRANASAL CORTICOSTEROIDS

Generic Name Dose (per Actuation) Minimum Approved Age Usual Dosing
Flunisolide 25 μg 6 yr Twice daily
Triamcinolone 55 μg 6 yr Once daily
Budesonide 32 μg 6 yr Twice daily
Fluticasone 50 μg 4 yr Once daily
Mometasone 50 μg 12 yr Once daily
*Intranasal corticosteroids are generally administered at two sprays per nostril.

Future Directions

 

Many patients have multiple antigen sensitivities, and specific immunotherapy at effective doses may not be practical. Furthermore, immunotherapy has poor efficacy for many antigens, such as molds. These issues have led to a search for new immune-based therapies capable of attenuating allergic inflammation. In addition to the future treatments discussed in the following paragraphs, many experimental approaches being developed for asthma, including various anticytokine therapies, hold the potential to provide efficacy for AR.

Anti–immunoglobulin E Antibodies (Omalizumab)

 

Omalizumab has been evaluated in the treatment of SAR. In patients with pollen-induced AR, anti-IgE significantly improved nasal symptom scores, use of rescue antihistamines, and quality of life. Clinical trials with omalizumab support its safety, including the absence of immune complex formation, serum sickness, or other significant untoward side effects. Omalizumab reduces the risk of anaphylaxis in patients who are receiving immunotherapy, a possibility that could lead to additional uses of this treatment. Reducing the risk of anaphylaxis could make immunotherapy available to high-risk patients with asthma and could plausibly increase the efficacy of immunotherapy by permitting utilization of even higher doses. At present, omalizumab is approved only for adults with moderate to severe asthma. The limiting feature of this therapy for AR will be its cost.

Novel Forms of Immunotherapy

 

Future strategies for immunotherapy are aimed at delivering increased efficacy with less risk for IgE-mediated systemic side effects. The challenge is to deliver a sufficiently high dose of protein to the T cell, to induce T-cell tolerance, without concomitantly delivering the allergen to mast cells in a form that can cross-link IgE and thereby induce anaphylaxis. Recognition of the importance of T-cell–dependent mechanisms in immune modulation after immunotherapy is leading to the development of reagents that interact with the T lymphocyte without engaging mast cell/basophil–bound IgE. Short peptide fragments derived from genetically engineered allergens have been successfully utilized in immunotherapy studies. These peptides retain the ability to be recognized and processed by antigen-presenting cells, to be presented to TH lymphocytes, and to drive the T cells into a tolerant state. Because these short peptides lack the complex structure of their parent compound, they cannot be recognized by mast cell/basophil–bound IgE and are generally not associated with risk for immediate-phase, anaphylactic responses. Studies with peptides in patients with cat and bee venom sensitivity have demonstrated induction of T-cell tolerance and therapeutic efficacy. However, these compounds have been frustrated by their tendency initially to activate allergen-specific TH2-like cells and thereby produce delayed allergic reactions including asthma exacerbations. More recent studies have utilized allergenic peptides coupled to synthetic bacterial DNA sequences. These are based on the concept that engagement of these immunostimulatory DNA sequences to their specific receptors (toll-like 9 [TLR9] receptors) provides a potent signal to drive the ensuing immune responses away from TH2 immunity. Initial studies have been extremely promising regarding efficacy, safety, and long-term immune modulation with these agents.

 

Copyright © 2007 Elsevier Inc. All rights reserved. –

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