Introduction
Allergic rhinitis (AR) is a common disease with 10% to 40% of adults affected. , In a sensitized individual, exposure to one or more allergens leads to a type 1, immunoglobulin E (IgE)-mediated, inflammatory response in the mucosal tissues of the upper respiratory tract. This leads to the classic symptoms associated with AR: nasal drainage (anterior or posterior), nasal obstruction, nasal itching, and/or sneezing. Classically, AR has been categorized as seasonal or perennial with seasonal symptoms seen in patients with sensitivities to outdoor plant allergens and year-round symptoms in patients sensitive to indoor allergens like house dust mites (HDMs) or dander from animals or insects. These categories can be inaccurate in patients with polysensitization and thus newer classification schemes have been proposed based on frequency and severity of symptoms. Intermittent AR is defined as symptoms for fewer than 4 days per week for fewer than 4 consecutive weeks, while persistent AR is defined as symptoms for more than 4 days per week for at least 4 consecutive weeks. Patients who experience reduced quality of life, impairment in daily activities (school, work, or hobbies), and/or disturbance in sleep due to AR are classified as having moderate-severe AR. Those without these issues are classified as having mild AR.
AR has traditionally been a significant driver of health care utilization in the United States. During the past several decades, however, the landscape has changed with the introduction of over-the-counter (OTC) medications for the treatment of AR. In 2007, prior to the availability of OTC intranasal corticosteroid sprays (INCS), there were upward of 17 million adult patients who sought care for AR in the United States. They were seen in health care settings three additional times and had nine additional prescriptions filled compared to their peers without AR. In 2013 the US Food and Drug Administration (FDA)-approved OTC INCS. This has fundamentally changed treatment patterns for AR. In 2018, fewer than 2 million patients were seen for management of AR in the United States, a 90% reduction in the number of patients being evaluated. In this landscape, it may be that patients seeking care for AR have more recalcitrant symptoms that are not fully resolved with available OTC medications. Today’s otolaryngologists need to be adept at allergy assessment and, in the appropriate setting, allergen immunotherapy (AIT) for the treatment of AR.
Indications
Allergy Testing
Importance of Clinical History
The term “allergy” refers to clinical symptoms following exposure to an allergen with an allergen-specific IgE (sIgE) interaction. Allergy tests are used to help determine whether a patient’s symptoms may be due to these exposures. This is important because many symptoms can also be attributed to other factors such as viral infections and irritant reactions. However, up to 50% of people will have detectable sensitizations on allergy testing. Thus, obtaining a good clinical history is the most crucial diagnostic test. If a patient lacks symptoms after exposure to a suspected allergen, they are unlikely to be diagnosed as “allergic.” The history should focus on the relationship between exposure to allergens and development of symptoms. It should also include the type, severity, timing, and duration of symptoms. Obtaining a good family history can help identify those patients at higher risk for developing allergies. When one parent has allergies, the risk of the child developing allergies is about 40% to 50%, compared to the approximate 20% risk in children without an allergic parent. When both parents have allergies, this risk may increase up to 90%. It is also important to obtain information about the patient’s comorbidities and all medications they are taking, both prescription and nonprescription.
When Clinical History Is Not Enough
Even with a thorough history, additional evaluation and testing are often required to diagnose allergy. Exposures may include more than one allergen simultaneously, and it can be difficult to determine which causes symptoms and which do not. Testing is also necessary to establish the diagnosis of allergy prior to initiation of AIT.
Contraindications to Skin Testing
There are numerous considerations when determining which patients are appropriate for skin testing. One such consideration is in patients with uncontrolled asthma. Patients with severe asthma, with persistent symptoms despite optimal pharmacological treatment, or forced expiratory volume in 1 second (FEV 1 ) less than 70% of the predicted value are generally considered high risk for skin testing. β-Blocker medications are a risk factor for treatment-resistant anaphylaxis, making the use of β-blockers a relative, but potentially serious, contraindication. Patients are generally asked to hold β-blockers for 24 hours before testing. Numerous medications can temporarily block skin test reactivity, namely antihistamines. Other classes of medications that may interfere with skin test reactivity include topical glucocorticoids, tricyclic antidepressants, benzodiazepines, H2 blockers, and omalizumab. In the case of omalizumab, suppression of skin test response can last several months. ,
Immunotherapy
When avoidance of the offending allergen is not possible and medical therapies are insufficient, AIT is a good option. Absolute contraindications to these treatments are similar to those of testing and are relatively few, mainly poorly controlled asthma. There are several other relative contraindications, including the use of β-blocker medications, active malignancy, active or uncontrolled autoimmune conditions, some immunodeficiencies, prior serious systemic reactions to AIT, eosinophilic esophagitis (for sublingual immunotherapy [SLIT]), and conditions that prevent the use of epinephrine (severe cardiac disease). Typically, AIT is not initiated in patients who are pregnant, but can be continued at consistent/maintenance doses in those who become pregnant after initiation. AIT dose escalation is not typically performed during pregnancy. Shared decision-making between the patient and treating provider may be used in certain cases to determine the best treatment option for patients in these circumstances.
Technique
Allergy Testing
Often the first step in allergy skin testing is the skin-prick test (SPT). This requires that a positive control (histamine) and a negative control (saline with or without glycerin) be introduced into the skin at separate sites. SPT is performed by introducing a droplet of antigen onto the skin and pricking through it, approximately 1 mm into the skin, with a skin prick device or high-gauge needle. SPT is quick and easily performed.
Intradermal testing is performed when diluted antigen extract is injected into the dermis, forming a superficial wheal. This type of testing is considered quite sensitive primarily because a larger volume of a known antigen concentration can be introduced. However, the greater volume of antigen that is delivered has more potential to precipitate an anaphylactic reaction and often select intradermal tests are applied following SPT to better delineate the patient’s reactivity to a particular allergen.
The blended technique incorporates the speed of SPT with intradermal testing to delineate allergen reactivity in a semiquantitative manner. The most well-known protocol is termed “modified quantitative testing” (MQT), and it involves combining the results of SPT and single intradermal testing to determine an “endpoint,” a potential starting point for AIT. The test is performed by first placing an SPT. Then based on those results, a single intradermal test using one of two possible dilutions is placed. The results of the SPT and intradermal tests determine an endpoint that is assigned for each antigen tested. ,
Several types of in vitro tests are available to measure a patient’s serum total IgE and slgE levels. These immunoassays are based on interactions between antigens and sIgE antibodies. , Recent advances in these tests have resulted in better sensitivity compared with prior versions. Advantages of in vitro serum tests include use in patients taking β-blockers, antihistamines, and other contraindicated medications, and who are unable to stop these before testing. It is also helpful in those with dermatographism or those who are hesitant to undergo skin testing.
Immunotherapy
AIT refers to disease-modifying treatments with persistent beneficial alterations in the patient’s immune system that decrease allergen reactivity upon future exposures. Subcutaneous immunotherapy (SCIT) or allergy shots are given with incrementally increasing doses at a set schedule over time during the escalation phase. Once a patient reaches his or her maintenance dose, they remain at that dose, receiving shots at specified intervals. Because AIT can cause severe reactions, including anaphylaxis, a physician should supervise trained personnel.
SLIT refers to drops or tablets dissolved under the tongue for 1 to 2 minutes, then swallowed. It provides a convenient, safe alternative to SCIT. While SCIT is typically given in a clinical setting due to the potential for life-threatening reactions, SLIT is considered safe for home administration. The most frequently and commonly reported side effect is the onset of oral/sublingual itching after taking the dose. As of 2013, no fatalities had been reported from SLIT. In some protocols, SLIT is also given in increasing doses until reaching a maintenance dose; however, the escalation phase is significantly shorter in SLIT versus SCIT. In other circumstances, patients initiate SLIT at the maintenance dose with no escalation required.
Outcomes
Allergy Testing
Published evidence is available regarding each form of allergy testing: SPT, blended techniques, and sIgE. Each method has positive and negative attributes, and there is no evidence that one method is clearly superior to the others. SPT is generally considered the safest form of skin testing. While there is a risk of anaphylaxis, there have been no reported deaths with SPT due to anaphylaxis. A recent meta-analysis reported the pooled sensitivity of SPT at 85% with a specificity of 77%. Due to the relative speed of application SPT may be a more appropriate option in pediatric populations. Blended skin testing combines SPT with intradermal testing, providing results that are both qualitative and quantitative. This quantitative data may decrease the time needed to reach therapeutic doses when used to initiate AIT. Sensitivity and specificity values for skin and serum sIgE testing vary widely between studies. Generally, skin testing has been considered more sensitive than in vitro testing and in vitro testing is considered more specific. The correlation between serum sIgE levels and results from both SPT and the nasal provocation test is also strong. However, due to laboratory variability, serum sIgE testing is considered by some as an alternative method reserved for use in those who cannot undergo skin testing.
Immunotherapy
Unlike symptomatic treatments for AR, AIT has been shown to result in long-term immunologic changes that lead to tolerance of allergens on reexposure. The mechanism of these immunologic changes is not fully understood, but several changes have been seen. There is a significant reduction in mast cell and basophil degranulation on allergen exposure and an increase in the number of regulatory T cells and B cells. There is a decrease in sIgE levels, and allergen-specific IgG-blocking antibody levels increase.
The outcomes of AIT are typically assessed by measuring changes in patients’ allergy symptoms and in the quantity of medications they use for the treatment of allergy symptoms. A recent meta-analysis of 26 double-blind randomized controlled trials evaluated outcomes of treatment with SCIT, SLIT drops, and SLIT tablets. All three treatment types lead to statistically significant decreases in symptom and medication scores when pooled. When treatments were directly compared, symptom score reduction was greater with SCIT than with SLIT drops or SLIT tablets. No difference in treatment outcomes was detected between patients treated with SLIT drops and SLIT tablets.
Prolonged treatment is needed to achieve sustained immunologic change and thus decreased symptom burden and medication need. Evidence suggests that a 3-year treatment course is the minimum length that leads to improvements that persist for at least a year after cessation of therapy. Treatment lengths shorter than this are associated with relapse of symptoms. While a hallmark of AIT is the importance of consistent, prolonged treatment, SCIT has been shown to be at least as potent as pharmacotherapy in controlling symptoms of seasonal AR as early as the first season following initiation of treatment.
There is strong evidence supporting the efficacy of AIT for the treatment of AR. , However, the potential for life-threatening anaphylaxis, albeit rare, and the cost and time burden associated with this treatment require a resolute commitment from patients. A thorough discussion of these considerations is key to appropriately selecting patients for this therapy.
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