The Immune System

The immune system is responsible for identifying and destroying elements foreign to the body while recognizing and protecting self, termed self-tolerance . It comprises the innate and adaptive immune systems.

The innate immune system is the first line of defense against potential invaders and is composed of barrier mechanisms, such as tight junctions along with cilia, defensins, lysozyme, and cells. Neutrophils, monocytes, mast cells, eosinophils, basophils, and dendritic cells work together through pattern recognition receptors to opsonize bacteria, activate coagulation and complement cascades, induce phagocytosis, and implement proinflammatory signaling pathways. This system is activated by foreign bodies and works quickly to help rid the body of infection.

The adaptive immune system is a more specific approach to protecting the body from infection. It is triggered when a pathogen evades the innate immune system. A new foreign antigen is presented to T cells and recognized as nonself, leading to the secretion of cytokines to recruit fresh macrophages, neutrophils, and other lymphocytes to the site of infection or spur the growth of additional T cells. T cells also secrete various molecules to induce B cells to produce specific antibodies via interleukin 4 (IL-4), or opsonizing antibodies via interferon γ (INF-γ).

Allergy Reactions

Allergy is caused by a type I hypersensitivity reaction, also termed an atopic reaction . This reaction is caused by excess production of IgE and begins with sensitization to the allergen, inducing IgE antibody production through T- and B-cell cascades. A family history of atopy, including asthma, eczema, hay fever, and urticaria, is a risk factor for the development of AR, asthma, and atopic dermatitis. Having one allergic parent leads to a 30% increased risk of having children with atopy, whereas having 2 allergic parents leads to an increased risk of 50%. Other risk factors include

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  Genetic susceptibility

  
  
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  Environmental factors

  
  
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  Exposure to allergens

  
  
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  Passive exposure to tobacco smoke

  
  
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  Exposure to diesel exhaust

Allergy reactions are split into 2 phases: early (humeral reaction) and late (cellular reaction). The early phase occurs within 10 to 15 minutes of exposure. Allergens deposited on mucosal surfaces are sampled by dendritic cells and migrated to lymph nodes for presentation to T cells for sensitization. Subsequent exposure results in antigen attachment to 2 IgE antibodies on mast cells, resulting in degranulation of histamine. High levels of mast cells in the mucosa of the respiratory and gastrointestinal tracts, the subconjunctiva of the eye, and the subcutaneous layer of the skin increases susceptibility at these sites. The inflammatory response leads to the release of histamine, leukotrienes, cytokines, prostaglandins, and platelet-activating factors. The histamine released is responsible for sneezing, rhinorrhea, itching, vascular permeability, vasodilation, and glandular secretions.

The late phase occurs 4 to 6 hours after exposure and is mostly a result of various cytokines and leukotrienes released from mast and T cells. These factors cause an influx of eosinophils through chemotaxis and can prolong symptoms and enhance the allergic cascade for up to 48 hours.

Hygiene Hypothesis

Several theories describe the pathophysiology of allergies, with the most prominent currently being the “hygiene hypothesis.” The hygiene hypothesis describes children raised in modern metropolitan lifestyles being relatively devoid of the natural microbial burdens seen by previous generations. These burdens may have prompted early immune maturation and prevented allergic disease and asthma from developing. Lack of immune maturation may be causing understimulated immune systems in infancy, allowing the “allergic march.”

The allergic march is a subset of allergic disorders, such as atopic dermatitis or eczema, food allergies, AR, and allergy-associated asthma. It is thought that nature may immunize against the allergic march through various microbial exposures of the respiratory and gastrointestinal tracts. As immune systems mature, the production of T lymphocytes increases. These increased numbers of T lymphocytes result in the increased formation of IFN-γ, which may inhibit mucous gland and smooth muscle hyperplasia, the fibrotic repair process, and mast cell activation.

Various studies have shown that increased exposure to various allergens may actually help decrease the incidence of allergic responses. A study performed by Svanes and colleagues showed that cat ownership helped decrease the number of atopic individuals developing asthma and dog ownership protected against the development of allergic asthma.

Classification and Symptoms

AR is separated into seasonal and perennial types. Seasonal AR is associated with various seasons depending on the allergen; the spring air is full of tree pollen, grasses dominate the air as summer begins, and weeds and molds fill the air in autumn. Symptoms vary throughout the year and are somewhat based on the pollen count; they consist predominantly of sneezing, congestion, watery rhinorrhea, and itchy eyes and nose.

Perennial AR is a more constant disease process. It is usually the result of allergies to dust mites, animal dander, mold spores, or cockroaches. The symptoms differ slightly from those of seasonal AR, with less sneezing, rhinorrhea, and eye involvement. This classification can be further divided into intermittent, with symptoms lasting for less than 4 days per week or less than 4 weeks, or persistent, with symptoms lasting for greater than 4 days per week or greater than 4 weeks.

Antihistamines

First-line medical therapy for allergy is usually antihistamines, which come in oral and nasal spray form. These drugs work as an H1 receptor antagonist, preventing histamine-induced reactions, such as vascular permeability, smooth muscle contraction, mucous production, and pruritus. Antihistamines have a good effect on early-phase reactions, but little effect on congestion. The first-generation oral antihistamines are notorious for causing sedation and impairing performance secondary to their lipophilicity, allowing easy crossing of the blood–brain barrier. These medications also cause significant anticholinergic side effects, including dry mouth, blurred vision, and thickened mucous. Second-generation antihistamines are generally less sedative, have a rapid onset within 1 hour, and produce fewer anticholinergic side effects. These medications do not cross the blood–brain barrier as easily, causing less sedation than their predecessors. However, these medications can still be sedative with increased dosage. Second-generation antihistamines are thought to change the conformation of the histamine receptor, deactivating it and providing longer symptomatic relief.

Intranasal antihistamine sprays, such as azelastine or olopatadine, have been approved for the treatment of allergies and vasomotor rhinitis. These drugs show rapid onset and good potency, with limited side effects, such as mild sedation and bitter taste. In a double-blind placebo-controlled study, Yamamoto and colleagues were able to show equal efficacy between oral and nasal antihistamines in regard to sneezing, rhinorrhea, and nasal congestion. However, olopatadine was more effective in controlling eye itching and watering. Hoyte and Katial evaluated various studies in their review and were able verify that these sprays were as efficacious or superior to oral second-generation antihistamines. Several recent studies comparing antihistamine nasal spray and nasal steroid sprays have shown increased efficacy of the antihistamine spray. Yañez and Rodrigo were able to show improved benefit in regard to ocular symptoms and nasal congestion when comparing intranasal antihistamines and intranasal steroids. No difference was seen between olopatadine and fluticasone when analyzing the total nasal symptom score (TNSS), including congestion, runny nose, sneezing, itchy nose, and ocular symptoms. However, olopatadine did display a faster onset of action, recorded by Patel and colleagues as less than 30 minutes compared with mometasone’s onset of action of 8 hours. These studies have shown nasal antihistamines to be superior to nasal steroids in the management of some symptoms; however, the combination of the 2 medications was shown to be superior to monotherapy with either medication in the reduction of TNSS.

Corticosteroids

Corticosteroids have long been considered to be the most effective pharmacotherapy for the treatment of AR. Intranasal versions have been shown to relieve sneezing, itching, rhinorrhea, and nasal congestion. Relief from these symptoms is usually achieved after 1 to 2 weeks of therapy, although effectiveness depends on regular use and adequate nasal airway for application. Nasal corticosteroids have no significant systemic absorption and some have been approved for use in patients aged 2 years and older. Side effects include dryness and epistaxis, which can be reduced through careful patient education. Occasional case reports have linked glaucoma with intranasal steroid use; however, a case-controlled study performed by Garbe and colleagues found no association. Systemic corticosteroids are often used for severe intractable symptoms in a tapering dose.

Decongestants

Decongestants are α-adrenergic receptor agonists that cause vasoconstriction, reducing turbinate congestion and improving patency of the airway. However, these medications have no effect on rhinorrhea, pruritus, or sneezing. Topical decongestant therapy is recommended for no more than 5 days because prolonged use can lead to rhinitis medicamentosa. Oral decongestants have less potential to elicit rebound rhinitis but have a broad range of side effects, including insomnia, anxiety, nervousness, irritability, tremulousness, restlessness, and headache. These medications should be avoided in patients with hypertension, arrhythmias, angina, urinary retention, or glaucoma.

Others

Intranasal saline irrigation has long been used as single-modality or adjuvant therapy for the treatment of AR. It has been found to be particularly useful in the presence of crusted nasal secretions secondary to chronic, thick drainage. A randomized study by Wang and colleagues examined the impact of nasal irrigation in children with acute sinusitis and found significant improvement in rhinorrhea, nasal congestion, throat itching, sleep quality symptoms, and nasal airflow. Another study of children found nasal irrigation to be additive to the use of intranasal glucocorticoids.

Intranasal anticholinergics, such as ipratropium bromide, help to control rhinorrhea but have little to no effect on other allergy symptoms. These medications act through blocking parasympathetic input to the nasal mucosa and relieving symptoms of rhinorrhea.

Mast cell stabilizers, such as cromolyn sodium (oral) and cromolyn sodium nasal solution, act through stabilizing the membranes of mast cells, thereby limiting the amount of histamine released during the early phase of an allergic response. The caveat to this medication regimen is that it must be used before the onset of symptoms and be continued throughout the entire exposure, usually every 6 hours.

Leukotriene inhibitors, such as montelukast, a specific antagonist of leukotriene receptors, are generally less effective than antihistamines and intranasal steroids but more effective than placebo.

Recombinant human monoclonal antibody to IgE, or anti-IgE therapy, with omalizumab, acts through binding circulating IgE molecules. The thought is that fewer molecules of IgE will be available to bind to mast cell receptors to precipitate an allergic reaction. This therapy is costly and the US Food and Drug Administration (FDA) currently approves its use only for moderate to severe persistent asthma in adults and children older than 12 years who have not experienced an adequate response to inhaled glucocorticoids.

One randomized trial evaluated patient response to omalizumab. Patients were randomly assigned to either subcutaneous placebo or various dosages of omalizumab every 4 weeks before ragweed season. Rhinitis symptoms were significantly improved in the highest-dosage experimental group. A dose-dependent decrease in free IgE levels was also seen with omalizumab use. Another trial randomized children to placebo or omalizumab after subcutaneous immunotherapy treatment and showed significantly lowered leukotriene release in the omalizumab plus immunotherapy group. These studies suggest the efficacy of using anti-IgE therapy to treat allergies.

Subcutaneous and Sublingual Immunotherapy

Immunotherapy has been used as a method to increase the threshold level of the appearance of symptoms after aeroallergen exposure though gradually increasing dosages of antigen. This method of treatment is indicated in patients who have inadequate control of symptoms with pharmacotherapy and/or allergen sensitivities. If no clinical improvement is seen in 1 year, reasons for lack of efficacy should be evaluated, such as ongoing significant allergenic exposures, continued exposure to nonallergen triggers, missing of clinically relevant allergens, and/or failure to treat with adequate dosages of allergens. If no reason can be found, the therapy should be discontinued.

Cox and Wallace recently published a review of immunotherapy articles. Subcutaneous immunotherapy (SCIT) has been used for a longer period, and therefore more information has been published on its use compared with sublingual immunotherapy (SLIT). Multiple trials have shown the efficacy of SCIT, and it is an accepted form of allergic therapy. However, larger concerns have been expressed regarding its safety. SCIT adverse reactions range from local to systemic. The local reactions of erythema, pruritus, and swelling are fairly common, occurring in 26% to 82% of patients and associated with 0.7% to 4.0% of injections. Systemic reactions can range from mild rhinitis to life-threatening anaphylaxis and occur in 2% to 7% of patients and with 0.2% of injections.

SLIT has become much more common in Europe than the United States. The benefits of SLIT are improved safety and the ability to home-administer compared with SCIT. American otolaryngologists were surveyed twice regarding reasons for not using SLIT, and responded with the lack of FDA approval as the number one cited reason, at 61.7% to 86.3%, and unknown effective dose as a distant second, at 27.5% to 43.9%. Although the effective dose has not yet been established, it is usually in the range of 300 times greater than SCIT dosing. Few studies have been performed comparing SLIT dosing frequency regimens, and none have compared the same dose administered at different frequencies.

In a meta-analysis analyzing 979 patients undergoing SLIT in 22 trials, Wilson and colleagues reported a significant reduction in symptoms and medication use. Furthermore, Penagos and colleagues was able to establish a significant reduction in symptoms and medication use in the pediatric population undergoing grass pollen SLIT therapy. SLIT has been shown to be safer than SCIT therapy, with a lower rate of systemic reactions overall and severe systemic reactions being very uncommon. However, local reactions are more common, with increased rates of oropharyngeal pruritus and/or mouth edema (46% and 18%, respectively). SLIT has also been associated with complaints of occasional abdominal pain, vomiting, uvular edema, and urticaria. In all of the trials and treatments, no deaths and only rare cases of anaphylaxis have been associated with SLIT.

In the treatment of grass pollen allergens, SCIT and SLIT are equally efficacious. In a comparison of 3 large clinical trials of grass tablets versus 1 large SCIT trial, when evaluating clinical parameters of SCIT and SLIT compared with placebo, reductions in symptoms of the immunotherapy arms were seen at 32% and 21% to 37%, respectively. Reductions in the use of pharmacotherapy of 41% and 29% to 46%, respectively, were also seen.

The mechanisms behind the effect of immunotherapy are unclear but are thought to be related to the production of blocking antibodies or a regulation of immune cascade. A review of various SCIT articles showed that most patients treated with immunotherapy show an increase in specific IgE with therapy. Various immunologic effects have been shown, including an increase in specific IgG, IgE-blocking antibodies, and specific IgE, with blunting of further seasonal increases in IgE, all or none of which may be responsible for the decreased response to allergen. Early events after immunotherapy include generation of T-regulatory cells, which may produce cytokines such as IL-10, IL-12, or transforming growth factor β.

Regardless of mechanism, studies have been able to link AR as a risk factor for the development of asthma, with up to 40% of patients with AR developing asthma later in life. Polosa and colleagues was able to show a significantly lowered incidence of asthma in patients treated with SCIT compared with pharmacotherapy alone 7 years after discontinuation of treatment. Another study evaluated 113 children with either SLIT or pharmacotherapy for 3 years and was able to show a 3.8-times greater risk of developing asthma in the pharmacotherapy group.