In this article, the authors review the current evidence regarding the public health and economic impact of allergic rhinitis. Diagnostic methods for allergic disease are discussed as well as certain nuances of allergy skin testing protocols. In addition, the evidence supporting sublingual immunotherapy (SLIT) for allergic rhinitis is reviewed, with subsequent attention to certain subgroups, such as adults and children, seasonal versus perennial allergens, and SLIT efficacy for individual antigens. The authors consider the evidence supporting appropriate SLIT dosing as well as the existing data on SLIT safety.
The following points provide the level of evidence based on the Oxford Center for Evidence-Based Medicine. Additional critical points are provided and the points here are expanded at the conclusion of this article.
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Sublingual immunotherapy (SLIT) reduces symptoms and medication use in allergic rhinitis. Subgroup analysis shows a benefit for seasonal and perennial antigens, adults and children, and higher antigen doses (evidence grade = 1a-).
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SLIT has shown a significant benefit for grass pollen and house dust mite antigens (evidence grade = 1a-).
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Recommended maintenance SLIT dosing for grass pollen is 15 to 25 μg major allergen per dose. Dosing for other antigens is not established (evidence grade = 1b).
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Most well-designed controlled SLIT trials have been performed with single-antigen therapy (evidence grade = 1b).
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The safety profile of SLIT for allergic rhinitis remains excellent (evidence grade = 1a-).
Disease overview: allergic rhinitis
Allergic rhinitis has a significant public health and quality-of-life impact in the United States. Using data extracted from the Agency for Healthcare Research and Quality 2007 Medical Expenditure Panel Survey, Bhattacharyya recently reported that 17.8 million adults in the United States (7.9% of the US population) sought care for allergic rhinitis in 2007. In this report, patients with allergic rhinitis were older, were more commonly female, had 3 more physician office visits, filled 9 more prescriptions, and had an overall health care expenditure totaling $1492 per person annually over persons without allergic rhinitis. Much of the increased health care expenditure for allergic rhinitis is allocated to pharmacotherapy, including antihistamines, decongestants, topical and oral corticosteroids, and others. Antigen avoidance measures are also advocated as an adjunct to the overall treatment plan for allergic rhinitis or perhaps as the sole treatment when a single-antigen trigger can be identified and avoided appropriately.
Antigen-specific immunotherapy is frequently used as part of the treatment paradigm for allergic rhinitis. Although sublingual immunotherapy (SLIT) was first reported in the United States in 1900, the primary modality of antigen-specific immunotherapy in the United States over the last century has been subcutaneous immunotherapy (SCIT). The benefits of SCIT for seasonal allergic rhinitis and perennial allergic asthma have been demonstrated in numerous randomized controlled trials and recent Cochrane reviews. However, safety concerns with SCIT remain. Systemic reactions with SCIT have been reported in 0.05% to 3.2% of injections and 0.84% to 46.7% of patients, including 23 near-fatal (5.4 per 1 million injections) and 3.4 fatal events per year (1 per 2.5 million injections). Concerns regarding systemic and fatal reactions with SCIT led the British Committee on the Safety of Medicines to question the safety of this immunotherapy modality in 1986. A surge of interest in alternative methods of antigen-specific immunotherapy followed. Immunotherapy methods, such as intranasal, bronchial, and oral administration, were investigated but none of these were as promising as SLIT because of the intolerable side effects or lack of efficacy.
SLIT has been a predominant immunotherapy modality in Europe for several years. However, over the last decade, clinical interest in SLIT has been growing rapidly in the United States. This increased interest and use of SLIT in clinical practice worldwide has also been accompanied by numerous randomized clinical trials assessing the efficacy of SLIT. This article reviews the evidence behind diagnostic testing for allergic rhinitis, followed by a discussion of the current evidence supporting SLIT for allergic rhinitis.
Evidence-based clinical assessment and diagnostic testing for allergic rhinitis
Allergic rhinitis is preliminarily diagnosed based on
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History
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Symptom complex
- •
Physical examination
Common symptoms of allergic rhinitis include intermittent clear rhinorrhea, sneezing, and pruritus of the nose. These symptoms may be accompanied by nasal congestion or obstruction and associated itching of the eyes and throat, watery eyes, and skin or pulmonary symptoms, among others. In the assessment of patients suspected of having allergic rhinitis, it is important to evaluate potential triggers by inquiring about the seasonality of symptoms; exacerbating environments or situations; family history of allergy or asthma; and other associated diseases, like rhinosinusitis, otitis media, and dermatitis.
Risk Factors for Allergic Rhinitis
Certain risk factors for developing allergic rhinitis have been described and may provide useful information as part of an allergic rhinitis history. These risk factors include a family history of atopy, first-born child or only child, cigarette smoke exposure, higher socioeconomic status, and total immunoglobulin E (IgE) more than 100 IU/L before 6 years of age. Physical examination findings of allergic rhinitis are relatively nonspecific and may also be seen with several other sinonasal conditions. Edema of the nasal mucosa, inferior and middle turbinate hypertrophy, and lymphoid hypertrophy of the Waldeyer ring may be seen with allergic rhinitis but may also be present in upper respiratory infections, rhinosinusitis, and nasal obstructive conditions. In short, physical examination findings may support the diagnosis of allergic rhinitis but should not be the sole diagnostic factor for this condition.
Patient History and Environmental Triggers for Allergic Rhinitis
It is important to remember that much of the initial assessment and treatment plan for patients with allergic rhinitis depends on patient history and environmental triggers even though items necessary for a complete allergy history and physical examination vary depending on the environment and geographic location in which patients with allergic rhinitis are being evaluated and treated. A thorough history and physical examination leading to a diagnosis of allergic rhinitis is often sufficient to guide initial avoidance measures and pharmacotherapy. However, if the diagnosis is in question, specific antigen reactivity information is desired, or allergen immunotherapy is being considered, skin or in vitro allergy testing should be undertaken.
Skin Testing for Allergic Rhinitis
Skin testing for inhalant allergy is based on the principle that once an antigen crosses the intact skin or mucosal barrier, the antigen will interact with mast cells in the tissue and cross-link adjacent specific IgE molecules. Depolarization of the mast cell ensues, and histamine is released in a dose-dependent fashion with respect to the antigen administered. This histamine release results in the classic wheal and flare reaction characteristic of the allergy skin test. Measurement of the wheal size allows a partially quantitative assessment of allergen reactivity. In vitro testing for IgE-mediated allergy may be undertaken as an alternative to skin testing. The first in vitro test for specific IgE was the radioallergosorbent test, or RAST test, reported in Lancet in 1967. Other examples of in vitro methods for the detection of allergen-specific IgE include ImmunoCAP and enzyme allergosorbent tests. Although the specific techniques used in each of these in vitro methods vary to some degree, a common principle involves the exposure of patients’ serum to typical antigens in the test assay. The patients’ IgE binds to these antigens and is then quantified via labeling and detection techniques specific to the individual assay. Quantification of allergen-specific IgE is possible because of the techniques used for in vitro allergy testing.
In the late 1980s and early 1990s, several articles were published comparing the advantages and disadvantages of skin testing and in vitro testing for inhalant allergies. In 1988, Ownby commented that the results of both skin an in vitro tests depend largely on the quality of the extracts used to perform the tests. Further, this article concluded that appropriately performed skin tests represent the best testing modality for the detection of allergen-specific IgE, whereas in vitro tests may be used in circumstances when the skin is not appropriate for testing, anaphylaxis is expected to occur with skin testing, or patients cannot discontinue medications that interfere with skin testing. With either skin or in vitro testing, the results of the test must be correlated with the patients’ history before making a decision regarding treatment. Although in vitro allergy tests are noted to be less sensitive than skin testing methods, the use of in vitro test results for allergen-specific immunotherapy has been shown to be safe in large clinical series. Further, although much of this literature dates back 20 or more years, many of the same arguments are used in comparisons of skin versus in vitro allergy testing today.
More recent evaluations of skin testing methods question certain aspects of testing protocols. In a 2008 review, Calabria and Hagan reported that the available literature at that time indicated that when a skin prick test is negative, a positive intradermal skin test did not correlate well with in vitro and challenge test results, therefore providing little additional information for the overall diagnosis. However, these investigators note that a negative intradermal skin test result seems to have a high negative predictive value. Krouse and colleagues generally agree that negative allergy screens by prick/puncture techniques are typically reliable with regard to the presence or absence of allergy. These investigators do note, however, that intradermal testing following a negative skin prick test may provide useful information if clinical suspicion for allergy remains high, especially in the case of mold antigens or unusual inhalant reactivity. Finally, special consideration should be given to skin testing for inhalant allergy when SLIT is planned. Because of the high safety profile associated with SLIT, in combination with short SLIT escalation protocols, quantification (or semiquantification) of allergy skin test reactivity is often unnecessary. Compared with skin testing for patients planning to undergo SCIT, in which intradermal dilutional testing is often performed to best determine patients’ specific endpoint for each antigen and shorten the escalation period as much as possible, patients on SLIT will have short escalation protocols with all antigens typically starting at the same dilution, thus obviating extensive dilutional skin testing.
Evidence-based clinical assessment and diagnostic testing for allergic rhinitis
Allergic rhinitis is preliminarily diagnosed based on
- •
History
- •
Symptom complex
- •
Physical examination
Common symptoms of allergic rhinitis include intermittent clear rhinorrhea, sneezing, and pruritus of the nose. These symptoms may be accompanied by nasal congestion or obstruction and associated itching of the eyes and throat, watery eyes, and skin or pulmonary symptoms, among others. In the assessment of patients suspected of having allergic rhinitis, it is important to evaluate potential triggers by inquiring about the seasonality of symptoms; exacerbating environments or situations; family history of allergy or asthma; and other associated diseases, like rhinosinusitis, otitis media, and dermatitis.
Risk Factors for Allergic Rhinitis
Certain risk factors for developing allergic rhinitis have been described and may provide useful information as part of an allergic rhinitis history. These risk factors include a family history of atopy, first-born child or only child, cigarette smoke exposure, higher socioeconomic status, and total immunoglobulin E (IgE) more than 100 IU/L before 6 years of age. Physical examination findings of allergic rhinitis are relatively nonspecific and may also be seen with several other sinonasal conditions. Edema of the nasal mucosa, inferior and middle turbinate hypertrophy, and lymphoid hypertrophy of the Waldeyer ring may be seen with allergic rhinitis but may also be present in upper respiratory infections, rhinosinusitis, and nasal obstructive conditions. In short, physical examination findings may support the diagnosis of allergic rhinitis but should not be the sole diagnostic factor for this condition.
Patient History and Environmental Triggers for Allergic Rhinitis
It is important to remember that much of the initial assessment and treatment plan for patients with allergic rhinitis depends on patient history and environmental triggers even though items necessary for a complete allergy history and physical examination vary depending on the environment and geographic location in which patients with allergic rhinitis are being evaluated and treated. A thorough history and physical examination leading to a diagnosis of allergic rhinitis is often sufficient to guide initial avoidance measures and pharmacotherapy. However, if the diagnosis is in question, specific antigen reactivity information is desired, or allergen immunotherapy is being considered, skin or in vitro allergy testing should be undertaken.
Skin Testing for Allergic Rhinitis
Skin testing for inhalant allergy is based on the principle that once an antigen crosses the intact skin or mucosal barrier, the antigen will interact with mast cells in the tissue and cross-link adjacent specific IgE molecules. Depolarization of the mast cell ensues, and histamine is released in a dose-dependent fashion with respect to the antigen administered. This histamine release results in the classic wheal and flare reaction characteristic of the allergy skin test. Measurement of the wheal size allows a partially quantitative assessment of allergen reactivity. In vitro testing for IgE-mediated allergy may be undertaken as an alternative to skin testing. The first in vitro test for specific IgE was the radioallergosorbent test, or RAST test, reported in Lancet in 1967. Other examples of in vitro methods for the detection of allergen-specific IgE include ImmunoCAP and enzyme allergosorbent tests. Although the specific techniques used in each of these in vitro methods vary to some degree, a common principle involves the exposure of patients’ serum to typical antigens in the test assay. The patients’ IgE binds to these antigens and is then quantified via labeling and detection techniques specific to the individual assay. Quantification of allergen-specific IgE is possible because of the techniques used for in vitro allergy testing.
In the late 1980s and early 1990s, several articles were published comparing the advantages and disadvantages of skin testing and in vitro testing for inhalant allergies. In 1988, Ownby commented that the results of both skin an in vitro tests depend largely on the quality of the extracts used to perform the tests. Further, this article concluded that appropriately performed skin tests represent the best testing modality for the detection of allergen-specific IgE, whereas in vitro tests may be used in circumstances when the skin is not appropriate for testing, anaphylaxis is expected to occur with skin testing, or patients cannot discontinue medications that interfere with skin testing. With either skin or in vitro testing, the results of the test must be correlated with the patients’ history before making a decision regarding treatment. Although in vitro allergy tests are noted to be less sensitive than skin testing methods, the use of in vitro test results for allergen-specific immunotherapy has been shown to be safe in large clinical series. Further, although much of this literature dates back 20 or more years, many of the same arguments are used in comparisons of skin versus in vitro allergy testing today.
More recent evaluations of skin testing methods question certain aspects of testing protocols. In a 2008 review, Calabria and Hagan reported that the available literature at that time indicated that when a skin prick test is negative, a positive intradermal skin test did not correlate well with in vitro and challenge test results, therefore providing little additional information for the overall diagnosis. However, these investigators note that a negative intradermal skin test result seems to have a high negative predictive value. Krouse and colleagues generally agree that negative allergy screens by prick/puncture techniques are typically reliable with regard to the presence or absence of allergy. These investigators do note, however, that intradermal testing following a negative skin prick test may provide useful information if clinical suspicion for allergy remains high, especially in the case of mold antigens or unusual inhalant reactivity. Finally, special consideration should be given to skin testing for inhalant allergy when SLIT is planned. Because of the high safety profile associated with SLIT, in combination with short SLIT escalation protocols, quantification (or semiquantification) of allergy skin test reactivity is often unnecessary. Compared with skin testing for patients planning to undergo SCIT, in which intradermal dilutional testing is often performed to best determine patients’ specific endpoint for each antigen and shorten the escalation period as much as possible, patients on SLIT will have short escalation protocols with all antigens typically starting at the same dilution, thus obviating extensive dilutional skin testing.
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