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Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)

Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)
Literature review current through: Jan 2024.
This topic last updated: Jul 06, 2022.

INTRODUCTION — Subcutaneous allergen immunotherapy (SCIT) may be administered using several different schedules. This topic review will discuss the advantages and disadvantages of accelerated immunotherapy schedules and the indications for their use and will provide several specific examples of protocols that have been used successfully for aeroallergen SCIT. There are few data addressing how frequently accelerated schedules are used by allergy specialists in different areas of the world.

Traditional SCIT schedules and accelerated schedules for Hymenoptera SCIT are discussed separately. (See "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring" and "Rush and ultra-rush venom immunotherapy for Hymenoptera allergy".)

TERMINOLOGY — SCIT is divided into two phases: build-up and maintenance. Accelerated schedules of immunotherapy involve shortening the length of the build-up phase, while the maintenance phase remains the same.

The build-up phase involves serial injections of increasing amounts of allergen. During this phase, tolerance to the allergen is gradually induced, and the patient's immune response to the allergen is modified from a T helper type 2 (Th2) phenotype to a T helper type 1 (Th1) phenotype [1]. In conventional SCIT schedules, the build-up phase involves one or two injections per week and lasts three to six months. Conservative and moderate examples of conventional SCIT schedules are shown (table 1A-B).

The maintenance phase of SCIT involves ongoing injections of an immunizing dose of allergen, usually at intervals of three to six weeks. During the maintenance phase, the immune transformation becomes complete. This phase is usually extended for a period of three to five years because shorter durations of treatment are associated with an increased likelihood of symptomatic relapse once therapy is discontinued [2].

The length of the build-up phase depends upon the frequency of the injections and the incremental dose increase between consecutive injections. Thus, accelerated schedules involve administering more injections per visit, increasing the dose more between consecutive injections, or both.

Accelerated schedules generally fall into one of two categories:

Cluster schedules — Cluster schedules involve the administration of several injections (two to three) of increasing dose at 30-minute intervals in one day (table 2). The patient typically returns on one or more nonconsecutive days, several days per week. Two days per week is a common approach, although up to four days per week (ie, every other day) is also possible. Maintenance is achieved in four to eight weeks, depending upon the spacing of the visits.

Rush schedules — Rush schedules involve administering injections of increasing dose at 15- to 60-minute intervals over one to three consecutive days until a target dose (usually slightly less than the maintenance dose) is achieved. The remainder of the build-up phase proceeds using a traditional schedule until maintenance is achieved, usually in less than eight weeks.

Ultra-rush immunotherapy is an even more rapid dosing schedule for immunotherapy, in which an effective maintenance dose is reached within one day. Ultra-rush is usually applied to Hymenoptera venom immunotherapy. Accelerated forms of venom immunotherapy are reviewed separately. (See "Rush and ultra-rush venom immunotherapy for Hymenoptera allergy".)

COMPARISONS WITH CONVENTIONAL IMMUNOTHERAPY

Advantages — Predictable advantages of accelerated schedules include increased patient convenience and more rapid induction of clinical benefit:

Greater convenience – Inconvenience is the most common reason patients discontinue conventional immunotherapy, and accelerated schedules involve fewer office visits.

More rapid onset of clinical benefit – Accelerated schedules induce the immunologic changes that occur during the build-up phase more rapidly than conventional schedules. Thus, patients experience clinical benefit sooner.

Reduced risk of dosing errors – Dosing errors are one of the leading causes of systemic allergic reactions during SCIT. Rush schedules involve fewer doses overall during the build-up phase, and these doses are administered over a more concentrated time period, so dosing errors are reduced.

Reduced cost – Rush schedules (although not cluster) involve fewer total injections and so can be less costly.

Potential disadvantages — Potential disadvantages of accelerated schedules include an increased risk of systemic reactions and possibly lower rates of long-term compliance with treatment.

Risk of systemic reactions – Systemic allergic reactions are more common with accelerated protocols compared with conventional schedules. (See 'Risk of systemic allergic reactions' below.)

Long-term noncompliance – Accelerated schedules usually result in a greater percentage of patients successfully reaching maintenance [3]. However, two studies have demonstrated reduced compliance with completion of three years of treatment. One study at a military medical center found that overall compliance was lower for patients on a rush schedule compared with those on conventional schedules (48 versus 80 percent) [4]. A study of a Korean nonmilitary population also found adherence was reduced for both cluster build-up and for ultra-rush compared with conventional schedules [5]. The reasons for this observation require clarification.

INDICATIONS — The indications for SCIT (of any type) are reviewed in detail separately. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy", section on 'Indications'.)

The indications for accelerated SCIT specifically are:

A desire by the patient to increase convenience of the immunotherapy process, and/or

A desire by the patient to experience clinical benefit sooner than would be possible with a conventional schedule

Multiple studies have demonstrated that clinically significant reduction in allergic symptoms is apparent shortly after reaching maintenance in patients receiving accelerated immunotherapy [6-9].

CONTRAINDICATIONS — Accelerated forms of immunotherapy should not be recommended to patients who are at increased risk for developing systemic allergic reactions in response to the injections or who have comorbid medical conditions that would reduce their chances of surviving anaphylaxis. Accelerated protocols are not appropriate for patients with any of the following:

Poorly controlled asthma – Poorly controlled asthma is one of the leading risk factors for developing a systemic allergic reaction during immunotherapy. Patients whose forced expiratory volume in one second (FEV1) ≤70 percent of predicted should not undergo accelerated immunotherapy, and studies have demonstrated that exclusion of these patients reduces the rate of systemic allergic reactions [10]. Clinical discretion is required in deciding to treat patients with FEV1 values of 70 to 80 percent of predicted, as data are limited about this group, whereas those with an FEV1 ≥80 percent may safely be included.

Increased sensitivity to the allergens to be administered – A careful clinical history is probably the best way to detect patients with extreme sensitivity. Most studies have not found a correlation between the size of reaction on skin testing and likelihood of systemic allergic reactions.

Medical conditions, other than asthma, which would impair the patient's ability to survive anaphylaxis or treatment for anaphylaxis – These conditions include cardiovascular disease and other pulmonary diseases.

Accelerated immunotherapy is also avoided in young children (under the age of five years) because higher rates of systemic allergic reactions were reported in this age group in at least one study [10].

RISK OF SYSTEMIC ALLERGIC REACTIONS — The primary disadvantage of accelerated immunotherapy schedules with aeroallergens is the increased risk of systemic allergic reactions during the condensed build-up phase. There are no convincing data that one type of aeroallergen is better tolerated than another (eg, perennial allergens versus pollens) in accelerated protocols.

Accelerated schedules for aeroallergen SCIT are associated with higher rates of systemic allergic reactions compared with conventional schedules, although most reactions are mild. The use of premedications can significantly reduce the incidence of systemic allergic reactions, but even with premedication and the fact that low-risk patients are generally chosen for accelerated protocols, systemic allergic reaction rates are higher than those of conventional schedules. In general, the most accelerated protocols have the highest rates of systemic allergic reactions.

Systemic allergic reactions occur in up to one-third of patients treated with rush protocols, even with premedication and careful patient selection, although most are mild. Specific protocols and reaction rates are reviewed below. (See 'Specific protocols (including premedications and safety)' below.)

Systemic allergic reactions occur in up to 6 percent of patients in most studies of cluster protocols. This rate is similar to that seen with most conventional SCIT protocols using traditional weekly build-up schedules and multiple allergens [11-17]. Systemic allergic reactions induced by SCIT using conventional schedules and risk factors for these reactions are reviewed in greater detail separately. (See "Anaphylaxis induced by subcutaneous allergen immunotherapy".)

With both accelerated and conventional schedules of SCIT, the risk of systemic allergic reactions is greatest during the build-up phase. The vulnerability seen during this initial phase has been attributed to the fact that the patient is exposed to even more of the allergen than at baseline because he or she is receiving it through the immunotherapy in addition to natural exposure before immunologic protection has been achieved. Therefore, shortening the build-up phase would be desirable in theory [18]. However, giving the same amount of allergen in a shorter period of time necessitates a more intense exposure, and patients are variable in their ability to tolerate this.

Systemic allergic reactions with accelerated protocols are uncommon following the first few injections. Instead, they tend to occur in the final doses of the 1:10 volume per volume (v/v) strength or in the 1:1 v/v strength (if the protocol extends into this strength).

A 2016 retrospective review of 11,982 patients compared systemic allergic reaction rates over five years for 9229 patients in a private allergy practice who received weekly build-up, 2576 who received nine-visit cluster, and 177 who were given two-day rush [11]. The cluster patients were premedicated with 20 mg prednisone, H1 antihistamine (dose not specified), and 10 mg montelukast. The two-day rush patients were premedicated with 40 mg prednisone, H1 and H2 antihistamine (dose not specified), and 20 mg of montelukast. With the weekly, cluster, and two-day rush protocols, systemic allergic reactions occurred in 2.8, 2.5, and 12 percent of patients, respectively, and 0.01, 0.06, and 0.33 percent of injections, respectively.

A large prospective study of 1152 patients (ages 3 to 63 years) compared the rates of systemic allergic reactions with a three-day rush schedule to those of a cluster schedule (ie, nine injections administered in six visits over two weeks) using a lyophilized dust mite extract. In addition, the impact of premedication, exclusion of patients with reduced forced expiratory volume in one second (FEV1), and adjustment for large local reactions were examined [10]. Subjects were premedicated with methylprednisolone, long-acting ketotifen, and theophylline. Among patients receiving dust mite extract, 36 percent had a systemic allergic reaction using a three-day rush schedule without premedication compared with 16 percent in the premedicated group. Systemic allergic reactions decreased to 7.3 percent when patients with FEV1 <70 percent of predicted were excluded and when the protocol was modified for large local reactions (>10 cm). Systemic allergic reactions occurred in 5.4 percent of those receiving the cluster schedule. Children under five years of age experienced greater rates of systemic allergic reactions than older patients, leading the authors to conclude that accelerated immunotherapy is not appropriate in this age group. (See 'Contraindications' above.)

Additional studies are reviewed below within the discussion of each type of accelerated schedule. (See 'Specific protocols (including premedications and safety)' below.)

When comparing different studies, it is important to realize that each protocol has several variables: the number of allergens administered, the type of accelerated protocol, the target dose (how close to maintenance the schedule aims to achieve), the premedication regimen, and the way in which systemic allergic reactions were measured. These details are reviewed with each study below. (See 'Specific protocols (including premedications and safety)' below.)

Interventions to reduce risk — Interventions to reduce the risk of systemic allergic reactions during accelerated immunotherapy include careful selection of patients, the use of premedications, and avoidance of initiation during peak pollen seasons in patients being treated with pollen allergens.

Patient selection — We suggest accelerated immunotherapy only to patients who are at relatively low risk for developing systemic allergic reactions to immunotherapy. We exclude patients who are unusually sensitive to one or more of the indicated allergens, have uncontrolled asthma, or have other comorbidities that would put them at risk for a poor outcome if a systemic allergic reaction were to develop. Contraindications to accelerated immunotherapy are discussed above. (See 'Contraindications' above.)

Premedication — Premedication is recommended to reduce the risk of systemic allergic reactions. We suggest the following:

Patients undergoing cluster immunotherapy should receive an H1 antihistamine prior to each injection visit. Many studies have used loratadine administered anywhere from 15 minutes to 2 hours prior to injections (peak serum concentrations of loratadine are achieved 60 to 90 minutes after dosing). (See 'Cluster schedules' below.)

Prior to starting a patient on rush immunotherapy (RIT), it is widespread practice to administer a glucocorticoid, in addition to an H1 and H2 antihistamine. Some protocols additionally call for antileukotriene agents. Different regimens have not been compared head-to-head. Premedications are usually administered for three days prior to the start of the protocol. Specific regimens that have been used successfully with certain protocols are discussed below. (See 'Rush schedules' below.)

H1 antihistamines — In a randomized trial designed specifically to study the impact of premedication with an H1 antihistamine on the safety of cluster SCIT, 45 adults were treated with either birch or Timothy grass aluminum hydroxide (slow-release) extracts, using a seven-week cluster protocol [19]. All patients had seasonal allergic rhinitis, and about 10 percent also had asthma. Subjects received loratadine (10 mg orally) or placebo two hours before each visit. Findings included the following:

There were significantly more systemic allergic reactions in the placebo group (79 versus 33 percent of patients).

The systemic allergic reactions in the placebo group were more severe (28 versus 6 percent of reactions were grade 3, which consisted of urticaria and/or asthma), although there were no life-threatening systemic allergic reactions in any of the patients.

There were significantly more dose reductions due to systemic allergic reactions in the placebo group compared with the premedication group (25 versus 9 reductions).

There were no differences between the two groups in the time to onset of systemic allergic reactions, suggesting that premedication did not delay the appearance of symptoms.

More patients in the loratadine group reached the maintenance dose (95 versus 71 percent).

There is some evidence that H1 antihistamines may enhance the efficacy of immunotherapy as well [20]. A proposed mechanism is that reduction of systemic histamine levels secondarily decreases levels of other immune modulators and shifts the immune response away from an allergic response.

Combination regimens — A small randomized trial evaluated the impact of premedication with a combination of agents or with placebo alone on 22 children undergoing a two-day rush protocol with different aeroallergens [21]. Patients in both groups received an average of 26 to 28 allergens in their immunotherapy solutions. Premedications were administered for three days, beginning one day prior to the two treatment days. Premedication consisted of astemizole (an H1 antihistamine that is no longer available), ranitidine (an H2 antihistamine that is no longer available in the US), and prednisone. Children ≥12 years of age received 15 mg astemizole twice daily for one day, followed by 10 mg twice daily the next day, and 5 mg twice daily on the third day. They also received prednisone (30 mg twice daily) and ranitidine (150 mg twice daily) on all three days. Younger children received age- and weight-adjusted doses. Seventy-three percent of children in the placebo group experienced systemic allergic reactions, compared with 22 percent in the premedication group, and the reactions were more severe, although all responded to treatment. The systemic allergic reactions began between 30 and 120 minutes after the injections, and the most common eliciting dose was 0.3 mL of 1:10 v/v. The incidence of local reactions was also reduced by premedication.

Following this study, most subsequent studies of rush protocols have used combinations of H1 antihistamines and glucocorticoids for premedication. Some also include H2 antihistamines and antileukotriene agents. The authors use a combination of H1 and H2 antihistamines and oral glucocorticoids. Different combination regimens have not been formally compared.

Omalizumab — Omalizumab has also been studied as a premedication for RIT, although this clinical application is not approved by the US Food and Drug Administration (FDA), and the agent is costly. A randomized trial of 159 patients examined the impact of omalizumab treatment (for 9 weeks before and 12 weeks after) on a one-day rush protocol with ragweed [22]. All patients also received fexofenadine. On the day of RIT, epinephrine was required to treat systemic allergic reactions in 14 percent of patients receiving omalizumab and immunotherapy, compared with 21 percent in the group receiving immunotherapy alone. (See "Anti-IgE therapy".)

Avoidance of peak pollen season — That there is an increased risk of a systemic allergic reaction when immunotherapy is given during the patient's allergy season was confirmed in a surveillance study [23]. For that reason, we do not recommend initiating accelerated SCIT during a pollen season if the patient is to receive injections for that specific pollen, because during this season, the patient is exposed to pollen in the air in addition to the doses of immunotherapy, resulting in an increased total cumulative dose of pollen exposure and an increased risk for systemic allergic reactions. Given that immunotherapy is a nonurgent procedure, all steps should be taken to perform accelerated SCIT during a time that is most convenient and safe for both the patient and the clinician.

Setting — Accelerated SCIT schedules were designed to be performed in the outpatient setting under the supervision of an experienced allergist and nursing staff. There are no data to suggest that patients should be routinely hospitalized to undergo accelerated immunotherapy safely. However, patients should be screened appropriately to exclude patients who are at increased risk. (See 'Contraindications' above.)

Modified extracts — The risk of a systemic allergic reaction with accelerated SCIT depends, in part, on the extract being administered. One modification that could reduce this risk is tyrosine adsorption. A study of 538 patients with atopic dermatitis and allergic rhinitis who received four increasing doses of tyrosine-adsorbed dust mite extract at two-hour intervals experienced 12 (2.2 percent) reactions, most of which were mild to moderate severity [24]. Tyrosine-adsorbed extracts are not available in the United States but are used in other countries.

OUR APPROACH TO RUSH IMMUNOTHERAPY — The following approach to rush immunotherapy (RIT) is based upon the authors' clinical experience with administering rush protocols over a period of 15 to 20 years. Practice parameters have not been developed specifically for accelerated forms of immunotherapy.

Our approach to RIT requires two nonconsecutive days. The first day is a pretreatment counseling session devoted to educating the patient and/or guardian, obtaining consent, and equipping the patient with appropriate premedications and an epinephrine autoinjector to take home after the injections are completed. The patient then begins the premedications and returns three days later for the injections, which comprises the second day of the protocol.

Staffing — The clinic staff should be trained in administering accelerated SCIT, be able to provide close monitoring, and be comfortable with the treatment of anaphylaxis.

Equipment — The following supplies and equipment should be available when administering RIT:

The patient's allergy extract, with the required dilutions.

Injection supplies (syringe, alcohol wipes).

Peak flow meter and spirometry equipment.

Equipment for monitoring vital signs (blood pressure cuff, stethoscope, and thermometer).

Supplies to obtain intravenous access and administer medications and fluids.

RIT administration forms.

Emergency medications (including weight-appropriate epinephrine autoinjectors and albuterol with nebulizer).

We also recommend having a dosing guide at the patient's bedside with precalculated doses of all anticipated emergency medications based on the patient's weight (particularly important for children), which have been reviewed by at least two health care professionals.

Pretreatment counseling — Patients present to clinic three days before the day that injections are to be administered. During this pretreatment counseling session, the following issues are addressed:

The clinician and family discuss the purpose of RIT and review the protocol to be used and the benefits and risks of the procedure.

Informed consent is obtained from the patient if older than 18 years of age. For children and adolescents 18 years of age or younger, we obtain consent from the parent or legal guardian.

The nurse and family discuss the epinephrine autoinjector and how and when it should be used.

The teaching record is signed by the patient and clinician.

The family receives prescriptions for premedication (glucocorticoid, H1 and H2 antihistamines) and for an epinephrine autoinjector.

Treatment day — On the day of the procedure, the patient and one adult guardian must be present. The patient and family must have signed the consent form. The patient must have taken the premedication as prescribed. The authors suggest that adult patients arrange for a companion to drive them home in case sedating antihistamines are administered during the treatment day.

The nurse obtains a height, weight, and baseline pulmonary function test.

The nurse takes baseline vital signs.

The nurse starts a heparin lock (this is controversial and is not always done).

The clinician examines the patient.

Some practitioners advocate skin prick testing with a histamine control prior to beginning the injection series. Response to histamine suggests failure to comply with the pretreatment medications [21].

The clinician begins the immunotherapy as scheduled on the immunotherapy forms.

The patient is carefully monitored for signs of local and systemic allergic reactions.

Peak flow readings are obtained before and 30 minutes after each injection.

Follow-up vital signs and pulmonary function tests are done as needed throughout the procedure.

The patient is observed for at least two hours after the final injection. If stable, the heparin lock is removed, and the patient is discharged with follow-up instructions to return in one week to continue build-up toward full maintenance immunotherapy.

ALLERGEN EXTRACT PREPARATION — The composition of the immunotherapy prescription and preparation of the extracts are not different from what would be used for conventional immunotherapy, although it is desirable to limit the number of injections required to deliver the relevant allergens. It is the authors' practice to use solutions mixed for each patient individually, combining compatible allergens, usually into one or two solutions. If this results in two solutions, we administer one solution per arm. In the authors' practice, we do not use more than two solutions, because the patient's arms already become quite sore from the multiple injections required.

Preparation of allergen extracts for use in SCIT is reviewed separately. (See "SCIT: Preparation of allergen extracts for therapeutic use" and "Allergen extracts: Composition, manufacture, and labeling".)

SPECIFIC PROTOCOLS (INCLUDING PREMEDICATIONS AND SAFETY) — The following protocols have been used successfully in clinical practice and reported in the literature. In these protocols, concentrations have been expressed for the purposes of comparison using an accepted nomenclature system, which calls for a volume per volume (v/v) representation (with 1:1 representing the undiluted maintenance concentrate "red vial") [15]. Some practitioners and older studies express concentrations using a weight per volume (w/v) nomenclature. In these studies, the maintenance concentration is expressed as 1:100 w/v. However, all of the tables in this review have been translated into the v/v system.

Ideally, concentrations are assigned a standard color vial used to represent that v/v concentration: silver 1:10,000, green 1:1000, blue 1:100, yellow 1:10, and red 1:1 [15]. This convention is used by most allergy practices.

Cluster schedules — A representative cluster schedule for aeroallergen SCIT is shown in the table (table 2) [25]. As mentioned previously, visits occur on one or more nonconsecutive days, several days per week. Two days per week is a common approach, although up to four days per week (ie, every other day) is also possible.

Most cluster protocols use an H1 antihistamine alone for premedication, as discussed previously. (See 'Premedication' above.)

The following studies of cluster protocols all included premedications:

In a study of 44 patients randomized to either aluminum hydroxide (slow-release) Timothy grass pollen extract or placebo, immunotherapy was administered using a cluster protocol of 11 injections given over four weeks [26]. All patients had severe allergic rhinitis during grass season, and 81 percent also had lower respiratory symptoms. All patients received loratadine, 10 mg orally, at least 15 minutes before each visit. There were no immediate systemic allergic reactions during the three-year study, which could be explained by the use of a slow-release allergen preparation, but there were delayed systemic allergic reactions, all of which were mild. During build-up, systemic allergic reactions occurred in 18 percent of the active therapy and 23 percent of the placebo injection group and during maintenance, 15 and 0 percent of the active and placebo injection groups, respectively.

A randomized trial to determine the most effective maintenance dose of standardized cat allergen immunotherapy (based on short-term immunologic changes and nasal challenges) used the protocol shown in the table (table 2) [25]. Active injections were administered to 21 patients, with another 7 patients receiving placebo injections. This study did not involve a prolonged maintenance phase. All subjects received loratadine two hours before each visit. There were no systemic allergic reactions.

A study designed to evaluate three different maintenance doses of cat allergen used a four-week cluster protocol administered to 28 patients, followed by one year of maintenance [27]. The schedule was the same as that used in the birch and Timothy grass trial mentioned previously [19]. Patients were premedicated with loratadine (10 mg) and zafirlukast (20 mg) two hours before each visit. Only one patient experienced a mild systemic allergic reaction (4 percent).

Another study compared reaction rates of 339 cluster patients who took four weeks to reach maintenance with 319 conventional SCIT patients who took eight weeks to reach maintenance [28]. Systemic allergic reactions were reported in 0.2 percent of injections and 1.5 percent of patients who received four-week cluster and in 0.7 percent of doses and 4.4 percent of patients who received the slower schedule. No severe systemic allergic reactions were observed in any of these patients.

A retrospective review evaluated reactions in 2576 patients who underwent a nine-visit cluster protocol [11]. Patients received prednisone (20 mg), H1 antihistamine (dose unspecified), and montelukast (10 mg) prior to each visit. Systemic allergic reactions were reported in 0.06 percent of injections and 2.5 percent of patients. Using the World Allergy Organization (WAO) systemic allergic reaction grading system, 51 percent of patients had skin or nasal symptoms (grade 1), 37 percent had lower airway symptoms (grade 2), 11 percent had respiratory distress or laryngeal edema (grade 3), and 1 percent had respiratory failure or hypotension (grade 4). No deaths occurred.

An analysis of 29 studies (of both aeroallergen and venom cluster SCIT) concluded that lower rates of systemic allergic reactions were associated with the following [29]:

Premedication given 15 to 60 minutes before the first injection of each visit (most studies used H1 antihistamines).

Use of a depot preparation (eg, aluminum-absorbed, not available in the United States).

Four or fewer injections per visit.

No fewer than four to six visits (compared with protocols of fewer clusters).

One or two visits per week, rather than three or four (with some evidence that two was safer than one).

Most studies of cluster immunotherapy have been performed with single allergens, and the published literature regarding the use of multiple allergens in cluster protocols is limited. However, the authors perform cluster immunotherapy with aqueous extracts and multiple allergens in their clinic using an H1 antihistamine for premedication and have had rates of systemic allergic reactions that are in keeping with the literature.

Rush schedules — Rush protocols involve building the patient up to a tolerated dose that is somewhat lower than the effective maintenance dose. Once this lower dose is tolerated, the remaining injections are given according to a traditional schedule of build-up until maintenance is reached.

Several different premedication regimens have been studied for RIT, all using an H1 antihistamine and oral glucocorticoid. Some protocols additionally use H2 antihistamines and antileukotriene agents. As discussed previously, different regimens have not been formally compared. (See 'Combination regimens' above.)

Various rush schedules have been described. It is difficult to compare them because of differences in extracts, final goal concentration, pretreatment regimens, and classification systems for systemic allergic reactions. However, we present examples of schedules that have been used successfully in practice and reported in the literature.

One- or two-day protocol with multiple aeroallergens

One study described a one-day rush protocol using multiple aeroallergens (including tree, grass, weed, mold, cat, dog, dust mite, and cockroach) administered to 22 patients (table 3) [30]. Reactions were seen in eight patients, of which five (23 percent) were systemic allergic reactions. Four received epinephrine, and all responded quickly to treatment. All were discharged after a two-hour observation in clinic, and none had biphasic reactions. The five patients who experienced systemic allergic reactions were switched to a conventional SCIT schedule for the remainder of their treatment.

A retrospective review of 65 patients evaluated the safety of RIT using multiple aeroallergens and mixes of standardized and nonstandardized allergens [18]. This study used a protocol similar to the one described above [30] and premedicated patients with prednisone, cetirizine, ranitidine (no longer available in the US), and either montelukast or zafirlukast. Systemic allergic reactions occurred in 25 patients (38 percent), of which 4 were moderate in severity and required epinephrine and 1 was severe (hypotension, facial angioedema, urticaria) and required epinephrine and intravenous fluids.

A later study modified the protocol used in the first study and reduced the rate of systemic allergic reactions to 2 percent (table 4) [31]. The modified protocol lowered the highest concentration of allergen reached on the first day by 10-fold (1:10 v/v instead of 1:1). In addition, patients were treated with a three-day pretreatment regimen of prednisone (20 mg twice daily for ages 1 to 12 years or 30 mg for ages >12 years, for three days) and a choice of antihistamine (cetirizine, loratadine, or fexofenadine, based upon patient/insurance preferences). The time between doses was lowered from 30 to 15 minutes. After the rush component was completed, build-up continued with a conventional weekly schedule until maintenance was reached, as in other rush protocols. In a report of 893 patients treated with this approach, 2 percent (18 of 893 patients) experienced systemic allergic reactions (which were not graded), although one-half of these reactions occurred during the conventional build-up phase, after the rush portion. One patient had anaphylactic shock and required epinephrine and hospitalization. However, the severity of this patient's reaction may have been increased by treatment of bronchospasm with bronchodilators alone, rather than epinephrine and bronchodilators.

A subsequent study using multiple aeroallergens in 138 patients used a similar one-day schedule consisting of eight injections over five hours and also stopped at 1:10 of the maintenance dose [32]. Patients were premedicated only on the initial day with prednisone, H1 blockers, and H2 blockers. Systemic allergic reactions were observed in 28 percent of patients or 1.3 percent of injections with 82 percent occurring after the last injection. This rate was similar to other studies and confirms that RIT is associated with a higher rate of systemic allergic reactions, even if stopped at this lower dose.

A review of reactions in 177 patients who underwent two-day RIT reported systemic allergic reactions in 0.33 percent of injections and 12 percent of patients [11]. Patients received prednisone (40 mg), H1 and H2 antihistamines (dose unspecified), and montelukast (20 mg) prior to each visit. Using the WAO systemic allergic reaction grading system, 62 percent of patients had skin or nasal symptoms (grade 1), 29 percent had lower airway symptoms (grade 2), 4 percent had respiratory distress or laryngeal edema (grade 3), and 4 percent had respiratory failure or hypotension (grade 4). No deaths occurred.

A 10-year review evaluated 362 adults treated with cat, dust mite, or weed pollen extracts using a one-day RIT protocol consisting of eight doses and ending with a dose of 0.5 mL of the maintenance extract. Pretreatment given the day before and the day of the procedure consisted of prednisone (40 mg), montelukast (10 mg) and a nonsedating H1 and H2 antihistamine (doses not specified) [33]. The investigators found a systemic allergic reaction rate of 13.8 percent, most of which occurred more than 30 minutes after the last injection. Risk factors for a systemic allergic reaction included lower body mass index, younger age, and a higher number of allergens in the extract.

In summary, there are several approaches to RIT, most of which result in systemic allergic reactions in up to one-third of patients, even with premedication and careful patient selection. However, the modified protocol (table 4) induced systemic allergic reactions at a significantly lower rate. The authors use a similar protocol in their own clinic (table 5).

ADJUSTING THE PROTOCOL FOR ADVERSE REACTIONS

Systemic allergic reactions — It is common practice to terminate cluster or rush immunotherapy (RIT) in a patient who develops a systemic allergic reaction and convert to a conventional schedule. Other approaches have not been reported.

As with conventional immunotherapy, patients who develop systemic allergic reactions should be treated for anaphylaxis and observed for a period of time once symptoms have resolved. Patients with mild-to-moderate systemic allergic reactions who respond promptly and completely to treatment can usually be observed in the clinic for two hours and discharged to home. However, it may be more appropriate to hospitalize a patient with a more severe reaction or with symptoms that do not respond promptly to treatment. Likewise, patients who live far from medical care or have little home support may be better served by hospitalization. There is a risk of biphasic reactions with anaphylaxis from any cause, and the risk factors for recurrent symptoms are unclear, although these have rarely been reported in the RIT literature. Deciding on the best immediate aftercare for a patient with a systemic allergic reaction obviously requires clinical judgement. (See "Biphasic and protracted anaphylaxis", section on 'Possible risk factors'.)

The patient should then return in one week to resume injections and should be changed to the conventional build-up schedule. We (the authors) believe it important not to extend this time period by even a few days, as it is our observation that patients who wait longer than one week tend to experience more systemic allergic reactions in the remaining build-up. We resume treatment with the dose that caused the reaction. Patients should premedicate with an H1 antihistamine prior to that visit and all future visits.

Large local reactions — Large local reactions are treated symptomatically (eg, with ice and acetaminophen), as with conventional immunotherapy. We do not terminate cluster or rush therapy for large local reactions, unless the patient is too uncomfortable to continue. In most cases, we wait a few minutes longer between injections to allow symptomatic treatments to start taking effect, and then continue the protocol.

INVESTIGATIONAL APPROACHES — A novel approach has been reported, in which the accelerated build-up portion of the immunotherapy is administered with a subcutaneous infusion pump, rather than as individual injections [34]. The study described 46 cat- and 20 dog-allergic patients who received three sessions (1:10 (v/v), 1:2 (v/v), and 1:1 (v/v) of the maintenance dose concentration) of subcutaneous infusions, each over 30 minutes, without premedication. This was followed by monthly maintenance injections. Of the patients who received cat extract, 8.1 percent had a systemic reaction; none of the dog-allergic patients had systemic reactions. These rates are comparable to the studies of other accelerated protocols with premedication, suggesting that infusions may be a safer way to administer the build-up doses. While this approach may provide greater control of extract absorption, further investigation is needed before it can be recommended, and it would be helpful to know if premedication could reduce the systemic reaction rate further.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)

SUMMARY AND RECOMMENDATIONS

Terminology – Accelerated schedules use a condensed build-up phase of immunotherapy to reach the maintenance dose more rapidly. The maintenance phase is unchanged compared with traditional schedules. (See 'Terminology' above.)

Cluster schedules involve the administration of several injections of increasing dose in one day. The patient returns on one or more nonconsecutive days, two to four days per week, and maintenance dose is achieved in four to eight weeks (table 2).

Rush schedules involve administering injections of increasing dose at 15- to 60-minute intervals over one to three consecutive days until a target dose (usually slightly less than the maintenance dose) is achieved. The remainder of the build-up phase proceeds using a traditional schedule until maintenance is achieved, usually in less than eight weeks.

Advantages – Accelerated schedules for subcutaneous aeroallergen immunotherapy (SCIT) offer increased patient convenience and more rapid onset of clinical benefit compared with traditional SCIT schedules. (See 'Advantages' above.)

Safety and contraindications – Compared with traditional aeroallergen SCIT schedules, accelerated schedules carry an increased risk of systemic allergic reactions. Accordingly, accelerated aeroallergen SCIT should not be offered to patients who are at increased risk for developing systemic allergic reactions in response to the injections or who have comorbid medical conditions that would reduce their chances of surviving anaphylaxis. (See 'Risk of systemic allergic reactions' above and 'Contraindications' above.)

Premedication – To reduce the incidence of systemic allergic reactions, we recommend premedication for all patients undergoing accelerated forms of immunotherapy (Grade 1A).

For patients undergoing cluster immunotherapy, we suggest an H1 antihistamine (Grade 2B). This is usually given 15 minutes to 2 hours before each visit. (See 'Premedication' above.)

For patients undergoing rush immunotherapy (RIT), we suggest a more extensive regimen of premedication that includes an H1 antihistamine and a glucocorticoid, starting at least one day before the day of injections (Grade 2C). Most protocols administer a combination of an oral glucocorticoid and H1 and H2 antihistamines, with or without an antileukotriene agent. (See 'Premedication' above.)

Preparation of extracts – Allergen extracts for use in accelerated immunotherapy are prepared similarly to those used in conventional immunotherapy, although the number of different solutions needed should be minimized. (See 'Allergen extract preparation' above.)

Example protocols

Cluster – Different protocols for cluster immunotherapy have been published, and a representative schedule is shown (table 2). However, studies evaluating the tolerability of cluster immunotherapy with multiple aeroallergens are lacking. (See 'Cluster schedules' above.)

Rush – Various protocols for RIT also exist. One protocol has been studied for use with multiple aeroallergens and is relatively well-characterized (table 4). The authors use a similar approach in their clinic (table 5). (See 'Rush schedules' above.)

Adjusting after a systemic reaction – We suggest that patients who develop systemic allergic reactions during accelerated immunotherapy be converted to a conventional schedule (Grade 2C). (See 'Adjusting the protocol for adverse reactions' above.)

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Topic 13526 Version 15.0

References

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