Introduction

Origin of the current practice of allergy immunotherapy (AIT) [1] is generally credited to Leonard Noon and John Freeman who collaborated in treating grass pollen–induced allergic rhinitis with subcutaneous injections of increasing doses of timothy pollen extract [2, 3]. Subsequently, due to its perceived efficacy and the absence at that time of alternative effective treatments, the practice was rapidly extended to many other aeroallergens and to perennial rhinitis and allergic asthma [4]. Even after efficacy of subcutaneous immunotherapy (SCIT) was proven in randomized, double-blind, placebo-controlled (RDBPC) trials [5, 6], the use of AIT was limited by the major investment of time and money and the real danger of local and systemic reactions to the treatment. These drawbacks to SCIT are in part addressed by the increasing use of sublingual administration (SLIT) that has a much greater safety profile, but further improvements, especially in the duration of treatment, are still the subject of active investigation. This paper will restrict its discussion to AIT with aeroallergens and to the two currently widely employed approaches, SCIT and SLIT.

Conditions for Which AIT is Clinically Effective

SCIT has been shown in systematic reviews and meta-analyses to be an effective treatment for allergic rhinitis, [7•] allergic asthma [8•], and Hymenoptera venom sensitivity [9], and there is some support for treating selected patients with atopic dermatitis who are sensitive to house dust mites (HDM) [10]. Similarly, SLIT has been found to be effective treatment for allergic rhinitis [7•], but the evidence for efficacy in allergic asthma is marginal [8•, 11] except for the HDM SLIT-tablets, where reduction in inhaled steroid use and exacerbations while improving asthma control have been demonstrated [12•, 13•]. The evidence for efficacy of SLIT in atopic dermatitis is similar to that for SCIT, but there are few studies that support the use of SLIT for Hymenoptera sensitivity [14], and its use for this indication is not recommended [15].

Patient Selection for AIT

AIT may be considered for patients with allergic rhinitis and/or allergic asthma who demonstrate specific IgE sensitization to allergens to which they are significantly exposed by in vivo or in vitro testing and where the pattern of exposure corresponds to the pattern of the patient’s symptoms. Symptoms should be of sufficient severity to warrant the expense and inconvenience of AIT and for SCIT the potential danger. Some practitioners would limit the use of AIT to patients whose symptoms are not adequately controlled by symptomatic medication. However, given the disease-modifying potentials of AIT, patients may opt for the long-term benefit, even if they are able to control their symptoms with pharmacotherapy.

Contraindications for AIT

There are several contraindications to placing a patient on AIT. Perhaps the foremost is the presence of severe or poorly controlled bronchial asthma [16•]. The European Academy of Allergy and Clinical Immunology (EAACI) guidelines list as absolute contraindications for SCIT the presence of uncontrolled or severe asthma, active systemic autoimmune disorders, active malignant neoplasms, and pregnancy and as ones where benefits must outweigh potential risks: partially controlled asthma, beta-blocker therapy, severe cardiovascular disease, systemic autoimmune disorders in remission, severe psychiatric disorders, history of poor adherence, primary and secondary immunodeficiencies, and a history of serious systemic reactions to AIT [17]. The US Immunotherapy Practice Parameters, 3rd update, differs from EAACI guidelines principally in making autoimmune disorders only a relative contraindication and stating that AIT should only be initiated if the patient’s asthma is stable with pharmacotherapy [18].

Although pregnancy is a contraindication for placing a woman on AIT, the treatment may be continued at the current dose if it is thought to be sufficiently high to provide therapeutic benefit, since it appears not to adversely affect the pregnancy or the fetus [19•].

There are no absolute lower or upper age limits, but there are additional considerations in the very young and very old.

Safety

Local injection- and oral ingestion-site reactions are common in SCIT and SLIT respectively. Large local injection-site reactions up to the size of the palm of the hand did not predict the occurrence of a systemic reaction with the next injection, so dosage adjustment is not necessary [20]. If local reactions are persistent and bothersome, two randomized, controlled studies showed that rinsing the syringe with epinephrine before drawing up the extract will decrease both their size and frequency [21, 22].

Oral symptoms such as throat irritation, mouth itching, or localized swelling of the mouth are quite common on initiation of SLIT, but each occurrence usually lasts less than an hour, and they become much less common after the first week or two [23].

An online survey covering SCIT administered in the USA between 2013 and 2016 reported systemic allergic reactions occurred in 0.6% of patients; most were mild-to-moderate in severity [24•]. The rate of severe, potentially life-threatening (grade 4) systemic allergic reactions was 0.00062% of injection visits and approximately 0.005% of patients treated with SCIT [24•]. The annual survey of SCIT-related SRs (2008–2018) gathered data on 64.5 million injection visits [16•]. Ten confirmed fatalities occurred during that period, 1 per 7.2 million injections. Systemic allergic reaction rates for SLIT-tablets between 0.06 and 0.4% have been reported, but, to date, no fatal reactions have been reported [25].

Because SLIT-tablets are taken at home, the US Food and Drug Administration (FDA) mandates that patients prescribed SLIT-tablets also be prescribed an epinephrine autoinjector to use should they have a SR after taking the tablet. Even if patients receiving SCIT wait in the medical facility for the recommended 30 min, an appreciable percent of SRs occur after leaving the clinic. For this reason, many US allergists prescribe epinephrine autoinjectors for their SCIT patients. The efficacy of this practice is limited by the observation that SCIT patients who have been prescribed epinephrine autoinjectors frequently do not use them when they do have a SR after leaving the clinic [24•].

Another controversial issue in the practice of SCIT is whether to reduce the dose administered during the patient’s pollen season. Survey results indicate that practices that routinely reduce doses during pollen seasons have fewer systemic reactions [26, 27]. However, 2 large studies failed to show that patients receiving grass or ragweed pollen extracts [28] or mountain cedar pollen extracts [29] had more systemic reactions during those pollen seasons than subjects not receiving those extracts in their treatment. Also, one hospital practice that began automatically reducing extract doses during the patients’ pollen seasons did not find that the change reduced the SR rate [30]. Thus, the issue is far from settled.

Modification by Medications of the Risk for Reactions

The rate and severity of both local and systemic reactions to both conventional and cluster SCIT is reduced by pretreatment with antihistamines [31, 32]. Pretreatment for a period of time with omalizumab reduced systemic reactions to rush AIT in patients with ragweed-induced seasonal allergic rhinitis [33] and to cluster AIT to cat, dog, or house dust mite extracts in patients with asthma who were receiving inhaled corticosteroids [34].

There has been concern about administering AIT to patients who are taking either beta-adrenergic blocking agents or angiotensin-converting enzyme ACE inhibitors. A recent observational study, which included 1425 patients with a history of a systemic reaction to an insect sting, found that B-blockers or ACE inhibitors neither increased the frequency of SRs during venom immunotherapy nor increased the severity of the reactions. [35]

Relative Efficacy and Safety of SCIT and SLIT

Dhami et al. conducted systematic reviews and meta-analyses on AIT for allergic rhinoconjunctivitis (ARC) [7•] and allergic asthma (AA) [8•]. They found 160 studies satisfying their inclusion criteria for ARC and 98 for AA. The comparative effects of SCIT and SLIT are shown in Table 1. Even accepting the limits of this comparison, the number of studies lends some support to greater effectiveness of SCIT over SLIT. However, a network meta-analysis of commercially available grass SCIT, grass SLIT-tablets, and grass SLIT-liquid preparations showed that for symptom scores, SCIT and SLIT-tablets had identical standardized mean differences (SMDs) which were significantly better than those for placebo, while the SMD for SLIT-liquid did not differ significantly from placebo [36]. For medication scores, the SMD for all three forms of AIT differed significantly from placebo. It appears that future meta-analyses should separately consider SLIT-tablet and SLIT-liquid preparations.

Table 1 Comparison of standardized mean differences (SMD) between SCIT and placebo and SLIT and placebo from meta-analyses [7•, 8•]
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Direct comparisons between the two routes of administration are uncommon and frequently methodologically flawed. However, two studies were conducted comparing the commercially available doses of 75,000 SQ-U timothy SLIT-tablets daily and 100,000 SQ-U administered subcutaneously either monthly [37] or bimonthly. [38] Both, using nasal allergen challenge as an outcome, found SCIT significantly more effective at the time of the first assessment, with non-significant superiority of SCIT over SLIT persisting the second year.

A factor possibly contributing to the greater efficacy of SCIT over SLIT is that adherence to SCIT, although not optimal, appears to be better than to SLIT. [39]

Mechanism of Action

The immunologic responses to SCIT and SLIT are similar and represent an allergen-specific shift from the abnormalities found in allergic patients towards the immune response found in non-allergic individuals [40]. After initiation of AIT, there is suppression of mast cell and basophil responsiveness and an increase in allergen-specific regulatory cells secreting the cytokine interleukin-10 (IL-10), these include not only regulatory T-lymphocytes, but also regulatory B cells, Treg follicular cells, and regulatory innate lymphoid cells [41•]. In addition, there is induction of iTr35 cells secreting IL-35 that are potential immune regulators [42]. These cellular changes are accompanied by suppression of specific immunoglobulin E (IgE) and enhanced production of specific IgG4 and IgA [40], with a serum-specific IgG4 response dominating with SCIT and both a serum and secretory-specific IgA response dominating with SLIT [43].

Changes also occur in the innate immune system with increases in innate lymphoid cells-1 (ILC1), intermediate- (L-10 producing) monocytes, and plasmacytoid dendritic cells and decreases in ILC2, ILC3, non-classical (proinflammatory) monocytes, and myeloid dendritic cells [44].

Later, there is an allergen-specific immune deviation from Type-2 to Type-1 cytokine responses to the specific allergen [45].

Disease Modification by AIT

Onset of Improvement

Improvements in nasal challenge and titrated skin tests were demonstrable after achieving maintenance dosing with SCIT in 5 weeks by a cluster regimen [46]. There was no further increase in outcomes following a year of maintenance SCIT, supporting the concept that it is the size of the individual dose of allergen, rather than the cumulative amount, that dictates the short-term response to AIT. With SLIT-tablets, where treatment is initiated with the maintenance dose, significant improvement over placebo has been demonstrated after 1 or 2 months [25]. Some, but not all, long-term studies have demonstrated increasing improvement with prolonged treatment. Progressively greater clinical improvement was seen in an environmental exposure chamber at 8, 16, and 24 weeks with a HDM SLIT-tablet [47] and during 3 Alternaria seasons with SCIT administration of a standardized Alternaria extract [48].

Duration of Treatment

Studies of 3 or 4 years of SCIT with grass pollen extract have shown good clinical responses and persistence of the improvement during 3 years of follow-up after AIT was stopped [49, 50]. On the other hand, a study of both SCIT and SLIT treatment for 2 years found that the improvement with both approaches was significant after 2 years versus placebo, but the benefit was largely lost 1 year after treatment was discontinued [37], suggesting 2 years of either SCIT or SLIT, even if clinically effective while being administered, was of insufficient duration to provide long-lasting relief. Other SCIT studies have shown that in patients with residual symptoms after 3 years, 2 further years of treatment produced significant further improvement in one [51] or produced no further improvement in the other [52]. A study with house dust mite SLIT found a good response with 3-year treatment, but a somewhat more prolonged remission following 4 or 5 years of treatment [53•]. Thus, the usual recommendation is 3–5 years of AIT depending on how quickly the patient responds, but stopping AIT if the patient has not responded by 1 year after reaching maintenance dosing.

Prevention of Additional Sensitizations

Several studies, all in monosensitized subjects but in both children [54] and adults [53•], have shown a marked decrease in the development of additional positive skin tests during and following a course of AIT of 3 years or more.

Reduction in the Risk of Developing Asthma in Patients with Allergic Rhinitis

The Prevention of Asthma by Treatment (PAT) trial administered grass or birch pollen SCIT for 3 years to children with AR due to those pollens. It was an open study, but there was an untreated control group [55]. The children were followed through 3 years of AIT and for 7 years follow-up. The children who had not received AIT were about 2 ½ times as likely to develop asthma, and the increased risk persisted throughout the 10 years of observation. A later study was conducted in children with a history of grass pollen-induced allergic rhinitis but no symptoms of asthma during a year of observation [56••]. Half the children received 3 years of a timothy SLIT-tablet, the others placebo, and all were followed for 3 years of treatment and 2 years of follow-up. The children treated with the timothy SLIT-tablet developed significantly less asthma, whether defined by symptoms, medication, use of inhaled corticosteroids, changes in FEV1, or any combination of these markers. Furthermore, the protection against development of asthma persisted through the 2-year post-treatment follow-up and was true for development of asthma during both the summer and the winter.

A review of European prescription databases for real-world evidence of the effectiveness of AIT identified 7 studies that examined the effect of AIT on the development of asthma in patients with only allergic rhinitis [39]. With up to 9 years follow-up, all preparations of AIT reported in the database showed decreased risk for developing asthma, in both children and adults.

Persisting Clinical Improvement After Completion of Treatment

Perhaps the greatest advantage of AIT over symptomatic treatment for either allergic rhinitis or asthma is the persisting clinical improvement that may last for years. This was demonstrated in a placebo-controlled study by Durham and co-workers [50] who randomized grass pollen–sensitized patients with allergic rhinitis, who had undergone 3 or 4 years of timothy SCIT, to either continue monthly maintenance injections of the grass pollen extract or to receive placebo injections for the following 3 years. There was no difference between active and placebo in symptoms or medication scores over the 3 years of observation. AIT was stopped in a similar group of grass-sensitive patients with allergic rhinitis who had had a good clinical response to 3 or 4 years of SCIT with grass pollen extract, and they were observed for relapse of symptoms [49]. The first grass pollen season 2.7% reported recurrence of symptoms, the second 16.7%, and the third 30.6%. The results emphasize that the duration of the continuing benefit is not the same in all patients, despite apparently similar responses to treatment. With SLIT, 3 years of treatment with timothy [57] or HDM [53•] extracts produced remissions that persisted several years following completion of AIT. Real-world studies also support persisting benefit of AIT for allergic rhinitis and asthma medication use, with follow-up periods of as long as 6 years [39].

Practical Considerations Concerning AIT

Treatment of the Polysensitized Patient

The majority of patients in both the USA and Europe presenting to an allergy clinic for evaluation of an allergic respiratory condition are sensitized to multiple aeroallergens [58]. There is no difference in the response to AIT with a single allergen, whether they are sensitive to only the allergen being used for treatment or to multiple unrelated allergens [59].

Treatment of the Polyallergic Patient

SCIT

A difference in the approach to the polysensitized patients comes when the patients manifest clinical symptoms to several of these allergens, that is, they are polyallergic. In Europe, most practitioners choose to treat polyallergic patients with the single allergen that is considered to be clinically most relevant [25]. This practice is supported by European guidelines, which do not recommend the use of mixtures of unrelated allergens [17, 60]. Instead, they recommend that only the most clinically important allergen extract be administered, or, if two extracts containing unrelated allergens are of equal importance, that they be given on alternate days or during the same visit in the left and right arm with at least a 30-min interval between injections. American allergists, on the other hand, regard the appropriate treatment of patients presenting with multiple allergies as opposed to just multiple positive skin as administration of a mixture of these allergens. This approach is supported by the small, but well-designed and executed studies by Lowell and Franklin in the 1960s [5, 6] and is embraced by the US Immunotherapy Practice Parameters, 3rd update, which recommend that patients be treated with a mixture(s) containing all clinically relevant allergen extracts. [18]

SLIT

The only approved allergen preparations for SLIT in the USA are the four SLIT-tablets. Surveys, however, have revealed a sizable group of US allergists who are prescribing sublingual administration of liquid extracts that are FDA approved for injection and skin testing [61]. The surveys did not determine whether these allergists are prescribing single or multiple allergen mixes for SLIT. Studies indicate that 2 SLIT-tablets can, after 4 weeks of separate administration, be given at the same time without undue adverse reactions [62]. Another study, with liquids, found that the efficacy of co-administered SLIT birch and grass was equal to the efficacy of each administered alone [63]. There is only one study, to my knowledge, that examines SLIT administration of a true multiallergen mixture [64•]. Subjects received either timothy diluted in saline, the same dose of timothy diluted to the same extent with 9 other pollen extracts, or placebo for 10 months sublingually. The outcomes titrated prick skin tests, titrated nasal allergen challenge, and specific IgG4 strongly favored the timothy monotherapy, with the timothy multiallergen mix barely outperforming the placebo.

Two Considerations in Multiallergen Treatment Extracts

Attention to Cross-Allergenicity

To prevent overloading the treatment extract with a group of cross-reacting allergens, either the locally predominating species should be used to represent a group of cross-reacting allergen extracts or a mixture of extracts of locally important members of the group should be prepared and treated as if it were a single pollen extract. Clinically important cross-reacting groups are listed in Table 2.

Table 2 Patterns of cross-reactivity of allergens.
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Avoidance of Mixing Extracts Containing Strong Protease Activity with Susceptible Allergen Extracts

Extracts of fungi and cockroaches have strong proteolytic activity [67] that can digest allergenic proteins in their own and other extracts [68]. The extracts of fungi differ greatly from lot to lot due to a high rate of somatic mutation [67]; therefore, apparent tolerance of mixing a potentially susceptible extract with a protease containing extract applies only to that batch of that fungal extract and cannot be extrapolated to other lots of the same fungus. For that reason, the safest practice is to not mix fungal or cockroach extracts with pollen, dander, or house dust mite extracts and not mix fungal and cockroach extracts [69].

Selection of Doses

There is a large placebo effect with AIT [70], so only the results of randomized, placebo-controlled studies can be used to determine truly effective doses. Such studies have been conducted with the development of the SLIT-tablets, they have been performed by SCIT with most allergen extracts that in the USA are standardized and a few non-standardized extracts; some SLIT studies have been performed in Europe with their liquid preparations, but there are few SLIT-dosing studies with US liquid extracts [71, 72].

One problem in determining effective doses is the lack of universally utilized units that reflect allergenic potency. It is generally recognized that the traditional weight/volume and protein nitrogen unit designations bear too little relation to potency to be useful for establishing guidelines. In Europe, each extract company has internal standards that are not translatable from one company to another. In the USA, the FDA has established standards among the inhalant allergen extracts for house dust mites (Dermatophagoides pteronyssinus and Dermatophagoides farinae), cat hair, short ragweed (Ambrosia elatior), eight grasses, and the Hymenoptera venoms, but cockroach, all fungal, all dander except cat, all tree, and all weed extracts except short ragweed remain non-standardized in the USA.

Although the measurement of component major allergen content of extracts is not, itself, standardized, the use of major allergen content is the only universally understandable expression of allergen extract potency. For this reason, many of the RDBPC trials that have been performed have expressed the maintenance dose in terms of the content of the major allergen of that extract (Table 3). This information is useful only if the major allergen content of the available extracts is known. This information has been provided by one of the US extract company’s (Tables 4 and 5). How does one use this information to formulate a treatment extract? If the maintenance vial is to contain 5 mL of treatment extract and the maintenance dose is 0.5 mL, then the vial must contain a total of 10 times the projected maintenance dose for each allergen. For example, the timothy maintenance dose should contain 20 μg Phl p 5 (Table 2) so the vial must contain timothy extract with 200 μg of Phl p 5; the stock timothy solution contains, on average, 620 μg/mL of Phl p 5. Dividing 200 by 620 gives approximately 0.3 mL of timothy 100,000 BAU/mL extract to be added to the 5-mL maintenance vial to deliver an adequate maintenance dose.

Table 3 Effective and less effective or ineffective AIT doses by subcutaneous injection [from reference 73]
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Table 4 Representative major allergen contents of US standardized and non-standardized pollen allergen extracts. [73]
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Table 5 Representative major allergen contents of US standardized and non-standardized environmental allergen extracts. [73]
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The Immunotherapy Practice Parameters, 3rd update, have used a similar database to generate recommendations for SCIT dosing with US extracts (Table 6). A range of doses are listed as probably effective; however, known major allergen contents of US extracts (Tables 4 and 5) suggest that the targeted dose should be at or slightly above the mean of the ranges suggested in the Practice Parameters. For non-standardized pollen extracts, the Practice Parameters recommend a 0.5-mL dose of 1:100 w/v or 1:200 w/v as maintenance, presumably aqueous or 50% glycerin extracts, respectively. For the cockroach and fungal extracts, there is no information on effective doses except for Alternaria, and all these extracts contain relatively small amounts of their major allergens [67, 74]. The Practice Parameters recommend for these extracts that the highest tolerated dose be given as maintenance.

Table 6 Range of probable effective doses of US standardized extracts (from reference 18)
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One message is clear, whether dosing is based on major allergen or recommendations of the Practice Parameters, single-allergen extracts not mixes of unrelated allergens should be used to compound the treatment extract. The only exception is for mixes of closely related allergens, such as the 2 house dust mites, 2 or more ragweeds, or northern pasture grasses. If such a mixture is used, it should be dosed as if it were a single allergen.

Selection of Type of Extract and Diluent

In Europe, many extracts are adsorbed to alum to slow systemic uptake and reduce systemic reactions, while some have been modified into allergoids by exposure to glutaraldehyde reducing their allergenicity while, hopefully, retaining their antigenicity. In the USA, there is only one line of pollen extracts that are alum precipitated and no allergoids. The main choice is between aqueous extracts and those containing 50% glycerin. The latter trades greater stability for pain with injection. For diluting concentrated extracts, the favored dilutent is saline containing 0.03% human serum albumen which helps preserve extract potency, particularly for dilute extracts.

Selection of Build-up Schedule

There is no build-up with the FDA-approved SLIT-tablets; treatment is initiated with the maintenance dose. This does require that the first dose be administered in a medical facility under the observation of a physician. For SCIT, a build-up to the maintenance dose is required. A slower than normal build-up schedule is recommended for subjects at increased risk of SRs, including those with marked sensitivity on skin testing, those with a history of a previous systemic reaction to AIT, and patients with consequential asthma. Two accelerated up-dosing schedules are employed to shorten the build-up period, cluster in which 2–3 injections are given on days separated from each other by non-treatment days and rush, in which multiple injections are administered on consecutive days reaching maintenance in one to several days. There is agreement that rush SCIT is associated with increased systemic reactions, even with premedication [75]. There is disagreement as to whether cluster is associated with an increased risk of systemic reactions [26, 76].

Modifications in Treatment

The dose of SCIT may require reduction under certain circumstance which include changing treatment to a new vial of extract, a systemic reaction, and a period of interruption in receiving injections. Recommended adjustments have been published [18], but there are no controlled studies that adequately address these issues.

Summary

Allergy immunotherapy is proven effective treatment for allergic rhinitis, allergic asthma, Hymenoptera venom sensitivity, and for some patients with atopic dermatitis and house dust mite sensitivity. Its efficacy depends on administration of adequate doses of the allergens. Effective doses have been defined for some allergens by SCIT, and they are well defined for the SLIT-tablets, but are largely unknown for SLIT-liquid extracts. While there is some evidence that multiallergen extracts are effective by injection, similar data supporting the efficacy of multiallergen extracts sublingually is lacking.