Andrea Ellen Nath and Fuad M. Baroody
Allergic rhinitis is a manifestation of the hypersensitivity of the nasal mucosa to foreign substances mediated through immunoglobulin (Ig) E antibodies. It usually manifests with nasal and eye symptoms, which include sneezing, runny nose, stuffy nose, itching of the nose, throat and ears, as well as eye tearing, redness, and itching. Because eye manifestations are often present, the disease is more commonly referred to as allergic rhinoconjunctivitis (AR). AR is the most common chronic condition in children and is most prevalent during school age. It is estimated to affect anywhere between 25 and 40% of the pediatric population in the United States with the highest incidence in the 13 to 14 year age group.1 During childhood, males are affected more often than females, but this gender distribution equalizes in adulthood. Most patients with AR develop symptoms before 20 years of age, with seasonal rhinitis rarely seen in children less than 2 years of age. This reflects the need for low exposure over a period of time to generate sensitization and clinical symptoms. Both a family history of allergy and a diagnosis of asthma increase the likelihood of developing AR.
Burden of Disease
Several studies have demonstrated significant impairment of quality of life in patients with AR and this applies to both generic and disease-specific measures. Disease-specific tools are more sensitive to change, with the rhinoconjunctivitis quality-of-life questionnaire developed by Juniper and colleagues being the most commonly used.2 There are modifications of this questionnaire that are used for perennial rhinitis in adolescents (12 to17 years old) and children (6 to 12 years old). AR also affects the emotional well-being, productivity, cognitive functioning, and school performance of affected children and adolescents. In a survey of 35,757 U.S. households—the Pediatric Allergies in America survey—subjects with nasal allergy between 4 and 17 years of age were targeted with various questionnaires aimed at their own as well as their parents’ perceptions of the effects of nasal allergies on daily life.3The responses were compared between children with and without allergies. A significantly lower percentage of children with nasal allergies were rated as having excellent health by their parents (43%) as compared with parents of children without allergies (59%). Similarly, lower proportions of children with allergies were described as “happy,” “calm and peaceful,” having “lots of energy,” and being “full of life” as compared with children without allergies. When looking at missed school or day care in the past 12 months because of allergies, health reasons, or both, the absenteeism rate was similar in children with and without nasal allergies. However, the proportion of children with diminished performance while at school as assessed by the parents was significantly higher in children with nasal allergies (40%) as compared with their nonallergic peers (11%). The parents of children with allergies also reported a 30% decrease in their children's productivity at school and at home when allergy symptoms were at their worst. When asked about effects of nasal allergies on sleep, parents of children with nasal allergies were twice more likely to describe sleep problems in their children as compared with the parents of children without allergies. Thus, when comparing children with nasal allergies to those without allergies, higher proportions of the children with allergies were reported to have difficulty falling asleep (32 vs. 12%), waking up during the night (26 vs. 8%), and lack of a good night's sleep (29 vs. 12%). The reported sleep disturbances associated with allergic rhinitis probably contribute to the significant negative impact of the disease on the quality of life of affected children.
In addition to the emotional and physical sequelae of the disease, AR imparts a significant economic burden related to the above sequelae, with direct costs to patients and insurance providers, and indirect costs that include absenteeism and decreased productivity. It is therefore estimated that the total economic burden of AR in children in the United States may be higher than US$ 5 billion a year.
AR is caused by an IgE-mediated hypersensitivity reaction that involves one or more allergens. The events involve a series of cellular and physiologic reactions that can be summarized as follows.4 During the initial stage of the disease, low-dose exposure of the antigen over a prolonged period of time leads to the production of specific IgE antibodies and sensitization. Antigen that is deposited on the nasal mucosa is taken up by antigen presenting cells such as macrophages, dendritic cells, and Langerhans cells. These cells partially degrade the antigen and the by-products are then presented to T-helper (TH) cells in the context of class II major histocompatibility complex molecules. Interleukin (IL)-1-activated TH cells then secrete cytokines, which promote other cells involved in the immune response. TH cells have varying phenotypes, the most common of which are differentiated by cytokine secretion. TH1 CD4+ cells secrete interferon-g and play a major role in intracellular pathogen clearance and delayed-type hypersensitivity. TH2 CD4+ cells are important in allergic reactions, secreting IL-4, IL-5 and IL-13, which are involved in the production of IgE and recruitment and survival of eosinophils at the sites of allergic reactions. Antigen-specific IgE then attaches to mast cells and basophils, sensitizing the nasal mucosa.
On repeated exposure to the allergen to which the individual is now sensitized, the IgE antibodies on the surface of mast cells and basophils act as receptors for the allergen and resultant cross-linking of the IgE receptors by antigen leads to the release of preformed (histamine and tryptase) and newly synthesized (leukotrienes, prostaglandins, platelet-activating factor, bradykinin, cytokines) inflammatory mediators (Fig. 9.1). The released mediators stimulate nerves, glands, and blood vessels and lead to the typical symptoms of AR namely, pruritus, sneezing, rhinorrhea, and nasal congestion. This sequence of events, referred to as the early phase response, has been supported by actual measurement of these mediators in nasal secretions during seasonal allergic disease and nasal allergen provocation experiments.
Figure 9.1 Schematic of the pathophysiologic events in allergic rhinitis. Cross-linking of immunoglobulin E receptors on the surface of mast cells by allergen in a sensitized individual leads to the release of mediators and the early phase allergic response. This is followed by cellular recruitment into the nasal mucosa and the late phase response. As a result of increased inflammation, the nasal mucosa becomes more responsive to repeated allergen exposure (priming) as well as to nonspecific environmental stimuli (nonspecific hyperresponsiveness).
The nasal response to allergen also leads to the stimulation of nasal reflexes by the inflammatory substances released during the early phase response. This leads to an amplification of the nasal response by the generation of a nasonasal reflex that is secretory in nature and mediated by the parasympathetic nervous system. Furthermore, these reflexes lead to the propagation of the allergic response to distant organs such as the eyes and the paranasal sinuses. In addition to the parasympathetic nervous system, several neuropeptides have been identified within the nasal mucosa in patients with AR and are thought to contribute to these reflexes.
Hours after the early phase response, there is a recurrence of nasal symptoms as well as the influx of inflammatory cells, notably eosinophils, into the nasal mucosa and nasal secretions, a phenomenon referred to as the late phase response. The levels of several cytokines including IL-4, IL-5, granulocyte-macrophage-colony-stimulating factors, IL-3, and IL-2 have been reported to increase within the nasal mucosa after allergen exposure. These cytokines are instrumental in orchestrating the allergic inflammatory response and are known to stimulate IgE production by plasma cells, as well as the recruitment and survival of inflammatory cells from the peripheral circulation into the nasal mucosa. Again, these processes are well documented by the recovery of these cytokines and inflammatory cells in allergic patients during seasonal disease as well as after experimental allergen provocation.
The above-described allergic inflammation results in a state of heightened responsiveness of the nasal mucosa. This translates into increased reaction to repeated allergen exposure, a phenomenon referred to as priming, as well as increased responsiveness to nonallergenic stimuli, such as histamine or methacholine, referred to as nonspecific hyperresponsiveness. Clinically, patients demonstrate worsening of symptoms as the allergy season progresses related to increased responsiveness to lower amounts of allergen related to priming. Patients can also exhibit an increased reaction after exposure to strong odors, pollution, or cigarette smoke during the allergy season, an example of nonspecific hyperresponsiveness.
Allergic rhinitis is often underdiagnosed in children due to their inability to communicate the duration of symptoms and subtle signs of allergic rhinitis. The most common symptoms of allergic rhinitis are recurrent episodes of sneezing, pruritus, rhinorrhea, nasal congestion, and watery and itchy eyes. Less common symptoms include itchy throat, itchy ears, and postnasal drip. When a large cohort of children with allergic rhinitis and their parents were surveyed, the reported frequency of nasal allergy symptoms during the worst month in the past year were quite similar between the parents and the children and were in descending frequency of occurrence: nasal congestion, repeated sneezing, runny nose, watering eyes, postnasal drip, red/itching eyes, nasal itching, dry cough, awakened/unable to sleep, headache, facial pain, and ear pain.3 The following symptoms were reported as most bothersome: nasal congestion (highest proportion), headache, runny nose, repeated sneezing, red/itching eyes, dry cough, postnasal drip, watering eyes, ear pain, nasal itching, and facial pain (lowest proportion). Therefore, it is clear that nasal congestion is the most common and also the most bothersome symptom of allergic rhinitis in children.
The disease has been classified differently in different guidelines and practice parameters. It is labeled as seasonal (symptoms occurring during specific seasons, e.g., spring [in patients sensitized to grasses and trees] and fall [in patients sensitized to ragweed]), perennial (symptoms occur continuously such as in individuals sensitized to indoor allergens [dust mite, indoor molds, and pets]), or episodic, a new category described in the most recent American guidelines (symptoms elicited by sporadic exposures to allergens [e.g., a cat-allergic individual who occasionally visits relatives who have a cat in the house]).5In an international set of guidelines developed in Europe under the auspices of the World Health Organization, the Allergic Rhinitis and its Impact on Asthma guidelines, allergic rhinitis is classified based more on duration and severity of symptoms.6 In these guidelines, allergic rhinitis is classified as intermittent (symptoms occurring less than 4 days a week or less than 4 weeks a year) or persistent (symptoms occurring more than 4 days per week and for more than 4 weeks in a year). Additionally the rhinitis is described as mild (the patient has normal sleep, daily activities, sport, leisure, work and school, and no troublesome symptoms) or moderate to severe (the patient has abnormal sleep, impairment of daily activities, sport, leisure, problems caused at work or school, and troublesome symptoms).
The clinician should establish the pattern and timing of allergic symptoms as well as assess the severity and interference with daily activities. Timing of symptoms during different seasons, or after exposure to certain pets, gives the physician an idea of the potential sensitizations of each particular patient. Perennial sensitization is a little more difficult to detect from history taking, but chronicity of symptoms may indicate perennial AR. History should also be elicited about home and school environmental exposures, as well as the effectiveness of any previous allergy therapy.
A complete ear, nose, and throat examination is required for children suspected of AR. Children with allergic rhinitis often exhibit the “allergic salute” in which the child uses their palm to rub the nose in an upward direction. Resorting to this behavior repetitively can lead to a supratip nasal crease. The patients will also demonstrate “allergic shiners” which are dark circles under the eyes related to venous congestion as a sequelae of chronic nasal obstruction (Fig. 9.2). Mouth breathing is a common symptom, especially in children who also have concomitant adenoid hypertrophy. Anterior rhinoscopy using the largest speculum of the otoscope or a nasal speculum is very useful in evaluating the inferior, and possibly, the middle turbinates. A pale nasal mucosal color is often very suggestive, though not pathognomonic, of allergic rhinitis, and children with allergies typically have clear, thin nasal drainage (Fig. 9.3). It is also important to evaluate the nasal septum for deviations that could be the source of fixed nasal obstruction and could exacerbate congestion in patients with coexisting allergic rhinitis. Nasal endoscopy can also be performed in the cooperative and willing child/adolescent. This examination allows the appreciation of all the changes seen with anterior rhinoscopy and adds a thorough evaluation of the middle meatus for signs of sinusitis or nasal polyposis, an appreciation of possible posterior septal abnormalities, and a good look at both posterior choanae and the adenoids. Examination of the oral cavity yields important information about possible postnasal drainage and the size of the tonsils which could contribute to upper airway obstruction, especially during nighttime.
Figure 9.2 Allergic shiners, a usual sequelae of chronic nasal obstruction in a child with allergic rhinitis.
Source: http://www.peds.ufl.edu/PEDS2/research/debusk/pages/page4_02.html. Printed with permission from the Department of Pediatrics, University of Florida.
Diagnostic Testing for Allergic Rhinitis
The most common diagnostic tools available are skin testing and in vitro testing for serum-specific IgE antibodies. Skin testing is performed by placing the allergen on the skin either intradermally or via a prick and observing for a reaction, which usually involves a wheal and flare in the sensitized subject (Fig. 9.4). A negative control consists of the diluent for the allergen extracts and a positive control is usually histamine, and both are placed on the skin in similar fashion as the allergens. Severity of the reaction is usually graded by comparison to the negative and positive controls. Most practitioners use prick testing routinely and reserve intradermal testing for the patient who tests negative to prick testing but has a very suggestive history. Skin testing is not reliable in individuals who have taken antihistamines or have certain skin sensitivity conditions such as dermatographism. Antihistamines have to be stopped (different periods for the different agents) before testing. Furthermore, some children are not amenable to multiple skin pricks. The risk of an anaphylactic reaction during testing is real but fortunately rare if appropriate recommended concentrations of allergens are used. In vitro testing for serum levels of IgE antibodies measure both total IgE levels as well as allergen-specific IgE levels. Radioallergosorbent test (RAST) is the most commonly used assay. While in vitro testing is less specific than skin testing, it is better tolerated (involves only one blood draw) and is not affected by medication intake, or skin conditions. Results of in vitro testing are usually available within 1 to 2 weeks whereas skin test results are apparent within 15 minutes. Total IgE levels are elevated in 30 to 40% of individuals with allergic rhinitis and a positive test alone does not confirm the diagnosis. Patients must have both a positive history as well as a positive test result. Choice of the technique used for allergy testing depends on the location of the practice, training of the practitioner and availability of facilities for the different types of tests.
Figure 9.3 Congested, pale, edematous nasal mucosa of a patient with allergic rhinitis. The inferior turbinates touch the nasal septum bilaterally (A) left nasal cavity and (B) right nasal cavity compromising the nasal airway.
Figure 9.4 Example of a positive skin-prick test in an allergic subject. (A) Application of a multipronged intradermal skin test device on a patient's forearm. (B) Test results interpreted 15 minutes after application of allergens. In this instance, the positive control (histamine) is depicted in the upper row all the way to the left and shows a positive wheal and minimal flare, the negative control (diluent for the allergen extracts) is depicted in the lower row all the way to the left and is negative. Two positive reactions are depicted in the upper and lower rows all the way to the right and show distinctly positive wheal and flare responses which are larger than that produced by histamine. The two allergens were tree and dust mite in this case.
Comorbid Conditions and Allergic Rhinitis
Several respiratory and airway conditions can affect children with allergic rhinitis. In the Pediatric Allergies in America survey, the children with nasal allergies were 2.8-fold more likely to have headaches, 7-fold more likely to have face pain/pressure, 11-fold more likely to report sinus problems, and 2.5 to 3-fold more likely to snore every day or on most days.3 Furthermore, children with allergic rhinitis were threefold more likely to have an asthma diagnosis and four times more likely to have had asthma in the past 12 months compared with their nonallergic counterparts.
Other studies have supported these findings. In fact, asthma is far more common in patients with allergic rhinitis than in those without, with as many as 50% of allergic rhinitis patients having asthma.7Sinusitis and rhinitis also often coexist and are usually referred to as rhinosinusitis. Allergic rhinitis is a risk factor for acute rhinosinusitis across all age groups. The inflammatory response associated with allergic rhinitis contributes to edema and impairment of sinus drainage and may be a contributing factor in as many as 30% of young adult patients with acute rhinosinusitis.8 Allergic rhinitis also commonly coexists with recurrent or chronic rhinosinusitis with 25 to 84% of patients with rhinosinusitis having concomitant allergic rhinitis.9
Acute otitis media and otitis media with effusion (OME) are among the most common problems of childhood. Several clinical studies have evaluated the association between allergic rhinitis and OME, with one series demonstrating a 21% prevalence of OME in unselected schoolchildren with allergic rhinitis10 and another finding a 50% prevalence of allergic rhinitis in children with OME.11 In one study of 209 children with a history of chronic or recurrent otitis media who had been referred to a multidisciplinary “glue ear/allergy” clinic, allergic rhinitis was confirmed in 89%, asthma in 36%, and eczema in 24%.12Skin tests were positive to one or more of eight common inhalant allergens in 57% of children, and, among those undergoing serum testing, peripheral eosinophilia was documented in 40% and an elevated serum IgE in 28%. Although there is a clear possibility of referral bias in this specialty population, the high frequency of allergy is notable. Furthermore, analysis of middle ear effusions and mucosal biopsies from atopic subjects with allergic rhinitis has demonstrated a pattern of inflammatory mediators not seen in nonatopic children, with significantly higher levels of eosinophil activity markers, mast cell products, and cytokines.
A link has also been postulated between adenoid hypertrophy and allergy via inflammation of the nasal mucosa, which is in direct proximity to the adenoids. A study found that the incidence of adenoid hypertrophy was almost twofold higher in children with allergic disease (allergic rhinitis, bronchial asthma, or atopic dermatitis) when compared with nonallergic controls (40 vs. 22%).13 Among those children with allergic disease, the incidence of adenoid hypertrophy was higher in children with allergic rhinitis, alone or coexisting with bronchial asthma (71%) compared with those children who had bronchial asthma alone (25%). The authors speculate that ongoing nasal inflammation from allergy could contribute to adenoid hypertrophy. Patients with allergic disorders of the upper airway often have significant sleep disturbances. While the mechanisms are not fully understood, congestion in the nose is presumed to be a key factor. Several epidemiologic studies have shown that allergic rhinitis is a risk factor for obstructive sleep apnea syndrome (OSAS) in children.14 In a group of children presenting to the sleep laboratory for the evaluation of symptoms of OSAS by polysomnogram, 36% had a positive RAST test. Furthermore, a significantly higher proportion of allergic children had an abnormal polysomnogram (57%) compared with nonallergic children (40%).15 It is therefore clear from these descriptive studies that allergic inflammation of the nose seems to be associated with similar inflammatory processes in other parts of the upper and lower airways. The effects that link these disease processes have been speculated to be related to multiple mechanisms including direct contiguity of the involved organs, systemic allergic inflammation, and neural reflexes.
Treatment of Allergic Rhinitis
Avoidance of allergens is beneficial but difficult to achieve to a significant degree, especially in the case of environmental allergens. For indoor allergens, avoidance is probably more practical. A Cochrane review found that use of high-efficiency particulate air filters, acaricides, mattress covers, and hot-water laundering to eliminate allergens significantly reduced symptoms of perennial allergic rhinitis.16 In another study, Morgan and colleagues evaluated the effect of environmental control on asthma symptoms in children where specific allergens were important in the genesis of these symptoms. The authors instituted interventions targeted at both indoor allergens and environmental tobacco smoke. They found that reductions in the environmental load of dust mite and cockroach allergens were proportional to a reduction in wheezing and significantly correlated with reduced complications of asthma.17
Antihistamines block the action of released histamine and are known to effectively control sneezing, itching, rhinor-rhea, and eye symptoms. These agents are not as effective in helping nasal congestion. First-generation antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine, brompheniramine, and clemastine) are lipophilic and cross the blood-brain barrier, thus leading to the notable side effect of sedation. They also have anticholinergic side effects which can lead to drying of secretions. Indeed, in a study evaluating learning scores in schoolchildren, allergic children receiving placebo were found to have lower scores than normal nonallergic children, suggesting a deleterious effect of allergic rhinitis on learning ability.18 When the allergic children received diphenhydramine, the sedating antihistamine for 2 weeks, their learning scores became even worse than the group on placebo and were significantly lower than nonallergic controls. In contrast, loratadine, a nonsedating agent, resulted in an improvement of learning scores that were not different from those of the control nonallergic group. To avoid such side effects, second-generation anti-histamines were developed (Table 9.1). They have reduced or absent anticholinergic side effects and do not lead to significant sedation, as they do not cross the blood–brain barrier. These agents are available in liquid form, and many are approved for use in children as young as 6 months of age. They have relatively rapid absorption and onset of action (within hours) and the longer half-life of the second-generation drugs allows once daily administration. Multiple clinical studies in children have documented the efficacy and safety of these drugs in allergic rhinitis. Intranasal antihistamines are also available for use in children (Table 9.1). Azelastine, a phthalazinone derivative, is available for the treatment of allergic rhinitis. Its efficacy is comparable to other antihistamines, and it might be more effective than oral antihistamines for nasal congestion. It is usually given twice daily, and can cause somnolence. Taste alteration may occur immediately after use with an incidence as high as 20%. Olopatadine hydrochloride (0.6%) has been shown to be safe and effective for the treatment of seasonal allergic rhinitis and is usually administered twice daily. The most commonly reported adverse reaction is bitter taste, and the incidence of somnolence is minimally higher than placebo vehicle.
Topical as well as systemic decongestants act to cause vascular constriction and reduce the nasal blood supply by alpha-adrenergic stimulation. Prolonged use of topical agents can lead to rebound nasal congestion, also known as rhinitis medicamentosa. Therefore their use should be limited to situations where severe allergic nasal congestion precludes the administration of other intranasal medications. In these cases, a short 3- to 5-day course of intranasal decongestants is used in conjunction with other intranasal agents (steroids, antihistamines) to facilitate access to the nasal mucosa. Oral decongestants are less effective than their intranasal counterparts, but do not cause rebound nasal congestion. Pseudoephedrine hydrochloride and phenylephrine are the most commonly used. Pseudoephedrine-containing decongestant products are now sold behind the counter in U.S. pharmacies because of the use of this medication in the illicit manufacture of methamphetamine. They are used most frequently in combination preparations with antihistamines (pseudoephedrine), or over the counter in cough and cold products in combination with analgesics and anti-tussives. Phenylephrine is another over-the-counter decongestant, also used in combination products. A recent meta-analysis showed lack of efficacy of phenylephrine on both objective and subjective measures of nasal congestion compared with placebo.19 In addition, their most common side effects are insomnia and irritability, which can be seen in as many as 25% of patients.
These agents are useful in the control of rhinorrhea associated with allergic rhinitis and have no therapeutic efficacy on any of the other symptoms of the disease. Ipratropium bromide is available for intranasal administration and lacks the systemic effects of atropine. It is used in patients with allergic rhinitis who continue to have significant symptoms of rhinorrhea despite maximal therapy with other agents.
Cromolyn sodium is a mast cell stabilizer and is available over the counter as a 4% solution for intranasal use in allergic rhinitis. It has been shown to be helpful for sneezing, itching, and rhinorrhea but not as effective for nasal obstruction. It does not cross the blood-brain barrier and is unlikely to cause sedation. It is noted to be safe in children and pregnant women but the need for frequent dosing reduces compliance and makes this agent less attractive as a therapeutic choice.
Because leukotrienes are generated in allergic rhinitis, the effects of inhibitors of the 5-lipoxygenase pathway and leukotriene receptor antagonists have been investigated. By far, the most commonly used agent in this category is montelukast which is approved in the United States for the treatment of seasonal and perennial allergic rhinitis in children as young as 6 months of age. Montelukast has repeatedly been shown to be more effective than placebo and equally effective as antihistamines for all ocular and nasal symptoms of allergic rhinitis, including congestion, rhinorrhea, and sneezing. Some, but not all, studies examining the combination of montelukast with an antihistamine (loratadine, desloratadine, cetirizine) have shown synergistic benefit.20,21
Intranasal steroids are considered the most effective treatment for allergic rhinitis, based, in large part, on their potent anti-inflammatory effects. In natural exposure as well as nasal allergen challenge studies, treatment with intranasal steroids inhibits symptoms, mediator release, T helper cell type 2 (Th2) cytokine expression, inflammatory cellular influx (notably eosinophils) into nasal secretions and the nasal mucosa, as well as hyperresponsiveness to allergen and nonspecific stimuli. These agents have been shown to be superior to both antihistamines and leukotriene receptor antagonists in the control of the symptoms of allergic rhinitis.22,23 Most guidelines suggest the use of these agents as first line in moderate-to-severe disease and even in some cases of mild allergic rhinitis. Efficacy begins at 7 to 8 hours after administration and starting these agents a few days before the start of the season has been recommended.
The principal side effect of intranasal steroids is local nasal irritation and epistaxis which occur in 5 to 10% of patients and septal perforations, although rare, have been reported. Biopsy specimens from the nasal mucosa of patients with perennial rhinitis who had been treated with such agents for 1 year showed no evidence of atrophy or epithelial injury. In the pediatric age group, studies looking at objective reproducible measures of growth (stadiometry or knemometry) and hypothalamic pituitary axis suppression after administration of intranasal steroids for periods up to 1 year, failed to show any adverse effects of the newer agents compared with placebo.24,25 Studies following intraocular pressure in patients on long-term intranasal steroids have failed to show a significant increase in intraocular pressure or the incidence of glaucoma compared with placebo.26 Based on these reassuring results, mometasone furoate and fluticasone furoate are approved by the U.S. Food and Drug Administration (FDA) for use starting at 2 years of age and fluticasone propionate starting at 4 years of age. Available agents and age of administration are listed in Table 9.2.
The role of systemic steroids in the treatment of AR is limited. Steroid pulses may be useful to help wean patients from topical decongestant use in cases of rhinitis medicamentosa. They can also be useful in cases of severe nasal congestion, given in 3- to 5-day courses, to enhance the penetration of concomitantly administered intranasal steroids.
Immunotherapy is allergen-specific repeated administration of increasing doses of antigen extract, either subcutaneously or sublingually, in an attempt to reduce a patients’ immunologic response. Immunotherapy is usually reserved for patients who have not responded to maximal multifaceted pharmacologic treatment.
Subcutaneous immunotherapy (SCIT), which has been used for decades, alters the immune response with suppression of immediate and late allergic reactions, as a consequence of suppression of infiltration of effector cells and subsequent mediator release. An immune deviation of allergen-specific T-cell responses from a Th2-biased in favor of a protective Th1-biased response has been observed. This seems to occur as a local immune event and has been associated variably with decreases in Th2 and increases in Th1 cytokines detectable in the periphery.27 More recently, it has been proposed that successful immunotherapy modifies the T-cell response to allergen through the induction of regulatory mechanisms, mostly regulatory T cells and their inhibitory cytokines IL-10 and transforming growth factor-beta (TGF-b). Support for this hypothesis comes in part from the description of populations of induced T-regulatory cells following SCIT and by the fact that allergen immunotherapy has been associated with upregulation of IL-10 and, variably, with increased TGF-b expression. Furthermore, local increases in IL-10–positive cells have been demonstrated within the nasal mucosa following SCIT.
As far as the humoral immune response is concerned, following an initial early increase in allergen-specific IgE concentrations during the updosing phase, SCIT results in blunting of seasonal increases in IgE and a long-term gradual reduction in serum allergen-specific IgE levels. On the other hand, SCIT is associated with marked and sustained increases in allergen-specific IgG1 and IgG4 antibodies and a more modest increase in serum allergen-specific IgA concentrations. The IgG antibodies produced after SCIT, specifically IgG4, possess blocking activity as evidenced by several studies. In one study, IgG and IgA antibodies from nasal washings of patients on SCIT were able to inhibit histamine release in vitro and in another, IgG4 antibodies produced following treatment blocked allergen-induced, IgE-dependent histamine release by basophils. Improvement of symptoms with SCIT starts within 12 weeks of initiation of therapy. A series of injections with increasing doses of allergen(s) over several months is followed by maintenance therapy that is typically administered for 3 to 5 years. There is ample evidence to support the clinical efficacy of this treatment modality for the symptoms of allergic rhinitis. In a meta-analysis which reviewed 1111 publications, 51 satisfied inclusion criteria and involved 2871 participants,28 there were no fatalities of SCIT, and active treatment resulted in a significant positive effect, compared with controls using outcomes of reduced symptom scores and use of rescue medications. Other studies have demonstrated a beneficial effect on quality of life. In addition to its beneficial clinical effects, SCIT has shown to be effective in the prevention of subsequent asthma in allergic children. In a study of 205 birch or grass allergic children 6 to 14 years of age treated with either SCIT or control, active treatment resulted in a significant improvement of symptoms and a significantly lower rate of asthma than the control group at the 2-year follow-up.29 In another smaller study, SCIT for 3 years resulted in a significant reduction in the development of new skin test sensitizations and the prevalence of seasonal asthma 12 years after therapy. Furthermore, SCIT is the only treatment of allergic rhinitis that has been shown to affect the natural history of the disease, with persisting clinical and immunological benefits several years after discontinuation of therapy.30 Despite its beneficial effects, SCIT involves systemic administration of allergen and has been associated with side effects, the worst of which are anaphylaxis and potentially death. In a review of the safety and efficacy of SCIT, epinephrine administration was required in 0.13% (19 of 14,085) injections, but no fatalities were seen.28 Other reviews suggest an incidence of fatal reactions from SCIT of 1 per 2.5 million injections or 3.4 deaths per year.
Because of the potential significant side effects of SCIT and the inconveniences of administration, sublingual immunotherapy (SLIT) has gained widespread attention over the past two decades. SLIT involves sublingual placement of small doses of the offending allergen. This route of administration is thought to limit side effects while maintaining benefits secondary to mucosal penetration. The majority of trials related to SLIT have been performed in Europe, and the therapy has not yet been approved by the FDA for clinical use in the United States. A meta-analysis of SLIT in children with AR which included 10 studies and 577 patients, demonstrated the clinical efficacy of SLIT with reduction in symptoms and medication use compared with untreated control patients.31 In a larger review of SLIT in adults and children with AR, 49 trials were included in a meta-analysis (2333 patients on SLIT and 2256 patients on placebo).32 The analysis again showed a significant reduction in symptoms and medication requirements in the actively treated subjects. None of the trials reported severe systemic reactions or anaphylaxis and none of the systemic reactions required the use of epinephrine.
Typical side effects of this therapy that have been reported are local oral (oral itching and swelling) and gastrointestinal reactions. Nonetheless, there have been isolated reports of more severe systemic reactions with SLIT, the most significant of which is a single report of anaphylaxis after SLIT.33 It is noteworthy that this patient had interrupted maintenance therapy for 3 weeks and then took a dose six times larger than the maintenance dose which precipitated the event.33
Like SCIT, SLIT has been shown to lead to positive immunologic effects and to modify the course of disease in children with rhinitis, conjunctivitis, and asthma. It can be administered for a limited period of time before and during a specific allergy season or on a year-round basis for perennial and multiple seasonal allergies. It carries the distinct advantage of being administered outside a doctor's office.
Allergic rhinitis is a common disease in children, and has significant signs and symptoms that affect the quality of life as well as their ability to concentrate and learn effectively in school. Available therapies are safe and effective and lead to an improvement in both symptoms and quality of life. These therapies range from environmental controls to pharmacologic therapy to immunotherapy. Clinical suspicion supplemented by specific diagnostic testing can identify the children who require allergy management.
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