ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Anaphylaxis induced by subcutaneous allergen immunotherapy

Anaphylaxis induced by subcutaneous allergen immunotherapy
Author:
David I Bernstein, MD
Section Editor:
John M Kelso, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Jan 2024.
This topic last updated: Sep 07, 2022.

INTRODUCTION — Subcutaneous allergen immunotherapy (SCIT) is an essential therapy in the clinical practice of allergy. However, it can induce anaphylaxis on rare occasions. This topic reviews the frequency, risk factors, and clinical features of systemic reactions to allergen injections, including fatal and near-fatal reactions. Strategies for management and prevention of anaphylaxis due to SCIT are also discussed.

The indications for SCIT, the treatment of anaphylaxis, and fatal anaphylaxis due to many different causes are discussed separately. Systemic reactions to sublingual immunotherapy are also reviewed separately. (See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy" and "Anaphylaxis: Emergency treatment" and "Fatal anaphylaxis".)

BACKGROUND — SCIT was introduced in the early 1900s. As early as 1916, systemic reactions were reported to occur with 3.5 percent of subcutaneous grass pollen injections [1]. In 1986, the Committee on the Safety of Medicines in the United Kingdom reported 26 SCIT-related anaphylactic deaths over a 10-year period [2]. This report led to adoption of a mandatory two-hour postinjection waiting period in the United Kingdom. This was difficult to implement and essentially eliminated the use of SCIT for years until a one-hour standard observation period became accepted practice. A 30-minute postinjection observation period is recommended in the United States [3].

FREQUENCY — The frequency of systemic reactions may vary according to type of allergens, potency of the injected allergens, mode of allergen preparation and modification, and dosing protocols (eg, accelerated cluster or rush build-up regimens compared with regimens with weekly build-up) [4].

Systemic allergic reactions (all severities) — The following studies provide estimates of the frequency of systemic reactions with different types of SCIT:

A systemic reaction rate of 0.025 to 0.4 percent of injection visits affecting 7 percent of treated patients was reported in two studies of SCIT with aqueous unmodified allergens using conventional build-up regimens with multiple allergens [5-7]. Most reactions were mild (generalized pruritus and urticaria only).

Results from a small, randomized trial suggest that the rate of systemic reactions may be lower with chemically modified extracts [8]. However, in two studies of SCIT with a limited number of allergens and using alum-adsorbed extracts, systemic reactions of varying severity occurred with approximately 0.1 percent of all injections and in 5 percent of treated patients, comparable with rates in North America where aqueous extracts predominate [7,9,10].

Reported systemic reaction rates were higher (4 percent of injections and in approximately 39 percent of treated patients) in earlier studies evaluating accelerated dosing regimens for aeroallergen SCIT, although severe anaphylactic reactions were still uncommon [11,12]. A retrospective study employing pretreatment (H1 antihistamine, montelukast, and prednisone) noted a lower systemic reaction rate of 0.06 percent for an accelerated cluster regimen, and 0.33 percent for a rush regimen, compared with 0.1 percent with a standard regimen [13]. The risks and advantages of accelerated immunotherapy are discussed in more detail elsewhere. (See "Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)".)

Fatal and near-fatal reactions — Fatal or near-fatal anaphylaxis after SCIT injections is a rare event.

Several retrospective surveys of fatal reactions and one survey of near-fatal reactions have assessed the frequency and nature of life-threatening anaphylaxis related to SCIT as practiced in North America [14-19]. Members of the American Academy of Allergy, Asthma, and Immunology (AAAAI) were contacted about occurrence of fatal reactions in their practices and indirect knowledge of such events occurring in other community practices. Responders reporting anaphylactic events were requested to complete a questionnaire regarding clinical manifestations of fatal reactions and near-fatal reactions, contributing factors, and subsequent management of anaphylactic reactions.

Fatal reactions — Fatal reactions have mostly occurred in adults, although there were consistently one or two children with fatal reactions reported in most surveys. Rates of fatalities range from one death in 2 million to one in 7.2 million injections:

Between 1985 to 1989, fatal reactions were estimated to occur once in every 2 million injections [16] and, from 1990 to 2001, once in every 2.5 million injections [17].

Between 2008 and 2018, fatal SCIT reactions were estimated to occur once in 7.2 million injection visits [19].

Near-fatal reactions — Near-fatal reactions involve respiratory failure or hypotension and correspond to World Allergy Organization (WAO) grade 4 reactions (table 1) [20]. Between 1990 and 2001, near-fatal reactions were reported at a rate of five per year or once every 1 million injections [18]. These data may underestimate or overestimate true incidences because of a low responder rate (approximately 25 percent), as well as potential inaccuracies in recall reporting and lack of verification of events occurring in other community practices.

Systemic reactions can occur in either the build-up or maintenance phases of immunotherapy, but in one large survey, the majority of near-fatal reactions and fatal reactions occurred during the maintenance phase (58 and 59 percent, respectively) [17,18].

There is some preliminary evidence that certain allergens may be more likely to induce severe systemic reactions or near-fatal reactions than others. In a multicenter Danish study of 1038 patients receiving monotherapy with alum-adsorbed extracts, Timothy grass pollen was the only allergen to induce severe (grade 3 and 4) systemic reactions, and this was noted at the highest allergen doses [21].

Web-based surveillance for anaphylaxis to SCIT — An annual web-based surveillance project (North American SCIT Fatality and Systemic Reaction Surveillance Project) cosponsored by AAAAI and the American College of Allergy, Asthma, and Immunology was initiated in 2008. It was intended to improve survey response rates and to track anaphylactic reactions with SCIT [22]. The survey captures data to estimate annual fatal reactions and mean and median numbers of SCIT injections administered, as well as frequencies of mild (grade 1), moderate (grade 2), and severe (grade 3) nonfatal systemic reactions. Participants were also asked if there were any fatal reactions due to SCIT or skin testing in their practice and if they had heard of any in the surrounding communities.

Data captured in the first 10 years (2008 to 2018) include the following [7,19,22-24]:

Systemic reactions occurred in 1 per 1000 injection visits and most are mild. On average, there were 6.7 grade 1 systemic reactions, 2.9 grade 2, and 0.4 grade 3 systemic reactions per 10,000 injection visits [23].

In year 3 of the survey, 72 percent of clinical practices reported mild (grade 1) systemic reactions, 57 percent experienced moderate (grade 2) systemic reactions, and 14 percent reported severe (grade 3) systemic reactions (table 2). The frequencies of mild, moderate, and severe reactions per injections visits were very consistent year to year from 2008 to 2011.

A total of 10 fatal reactions were reported in the United States from 2008 to 2018 [7,19,24]. This includes three fatal reactions reported between 2008 and 2016 in association with an estimated 54 million injections. From 2016 to 2018, an additional seven fatal reactions were reported, suggesting an unexplained increase in SCIT-related fatal reactions [24].

Severe systemic reactions (grade 3) represented 3 to 4 percent of all reported systemic reactions over the first three years of the SCIT surveillance study [23].

Late-onset reactions beginning more than 30 minutes after injections accounted for 14 percent of all reported systemic reactions in year 2 of the SCIT safety surveillance study. Although 12.5 percent of severe reactions began after 30 minutes, all were managed successfully [25]. This was confirmed during years 7 to 8, in which 15 percent of all systemic reactions began after 30 minutes. However, only 4.8 percent of the delayed-onset systemic reactions were graded as grade 3 or 4 in severity by the WAO criteria [24].

Clinical practices that experienced severe anaphylaxis were significantly more likely to use a higher dose range of house dust mite extract (1000 to 1999 allergen units) when compared with practices experiencing only mild systemic reactions to allergen injections [26].

Practices that always adjusted maintenance doses of injections during peak pollen seasons were significantly less likely to report grade 3 or 4 systemic reactions [7].

Practices that tracked the observation time after SCIT injections and required patients to check out with office personnel had significantly lower rates of systemic allergic reactions compared with those using other post-injection monitoring strategies [19].

Accelerated rush build-up regimens were associated with more grade 1 and grade 2 systemic reactions than slow build-up regimens [23]. Specific cluster build-up protocols with premedication may have comparable rates of systemic reactions as slow build-up [13]. There was no association with grade 3 or 4 reactions, but too few of these occurred to assess.

A prior history of a SCIT-related systemic reaction was reported among 26 percent of all patients experiencing a systemic reaction of any severity. In those patients with SCIT-related anaphylaxis, 34 percent had experienced a prior systemic reaction to SCIT [27].

CLINICAL CHARACTERISTICS

Signs and symptoms — Systemic allergic reactions to SCIT range from cutaneous manifestations (pruritus, urticaria, or angioedema at locations other than the site of the injection) to anaphylaxis (figure 1). The World Allergy Organization has issued a grading system for classifying clinical severity of systemic reactions to SCIT specifically (table 1).

Life-threatening reactions — Life-threatening anaphylaxis after SCIT injections is characterized by severe bronchospasm with acute respiratory failure and/or hemodynamic compromise manifested by profound hypotension and associated symptoms (syncope, collapse). (See "Fatal anaphylaxis".)

Similarities and differences in clinical presentations of fatal reactions and near-fatal reactions were apparent from clinical data collected in two American Academy of Allergy, Asthma, and Immunology-sponsored surveys (figure 2) [17,18]:

Hypotension was a common feature reported in greater than 80 percent of fatal reactions and near-fatal reactions. Shock, syncope, or cardiac dysrhythmia occurred in 69 percent of fatal events reported in a prior fatality survey [15].

Cutaneous manifestations (urticaria, angioedema, and pruritus) occurred at a much higher frequency in near-fatal reactions (70 percent) than in fatal reactions (29 percent). Absence of skin manifestations may result in delayed recognition and treatment of fatal reactions.

Upper airway obstruction (eg, angioedema) and bronchospasm were reported with similar frequencies in fatal reactions and near-fatal reactions. However, acute respiratory failure was identified in 94 percent of fatal reactions, compared with 10 percent of near-fatal reactions. This difference probably reflects the higher prevalence of uncontrolled asthma documented among patients with fatal reactions. All patients with fatal reactions and near-fatal reactions who developed respiratory failure were previously diagnosed with asthma. Over one-half of patients with near-fatal reactions who required intubation had preinjection forced expiratory volume in one second values <70 percent of predicted [18].

Timing — There are a number of reports indicating that one-half to two-thirds of all systemic reactions due to SCIT start within 30 minutes from the time of injection [5,10,28-30]. Late reactions may be overestimated in the later reports, as the North American SCIT Fatality and Systemic Reaction Surveillance Project estimated that approximately 85 percent of systemic reactions begin within in the first 30 minutes [25]. The remainder starts within six hours from the time of the injection.

Examination of the most serious reactions reveals that 96 percent of near-fatal reactions and 90 percent of fatal reactions began within 30 minutes after allergen injections in the North American surveys [15-18]. Thus, about 10 percent of fatal reactions were reported to have started 30 to 60 minutes after injections [15-17].

In one report, late reactions beginning after 30 minutes occurred more frequently among patients with asthma receiving injections of multiple allergens [30]. Consistent predisposing factors have not been identified.

Biphasic reactions can occur. In prospective studies, 10 to 23 percent of anaphylactic reactions to SCIT were biphasic [31,32]. The second phase of these reactions was mild and did not require treatment with additional epinephrine. In one of the studies, low baseline peak expiratory flow and concomitant asthma were associated with biphasic anaphylaxis [32].

FACTORS ASSOCIATED WITH FATAL AND NEAR-FATAL ANAPHYLAXIS — Clinicians reporting fatal reactions and near-fatal reactions were queried about factors they believed contributed to risk for these events as part of three retrospective fatality surveys. A summary of responses combined from two studies is shown in the table and reviewed below (table 3) [16,17]. In one of the surveys, clinician responders could not identify an explanation or contributing factor in 17 percent of fatal SCIT reactions [17].

Asthma — A pre-existing diagnosis of asthma was more frequent among patients with fatal reactions (88 percent) compared with those with near-fatal reactions (46 percent) [18]. In addition, indicators of uncontrolled asthma were more common among patients with fatal reactions compared with near-fatal reactions, including reports of poor asthma control, labile asthma, prior emergency room visits, and prior hospitalization (figure 3) [18]. Four of seven SCIT-related fatalities occurring between 2008 and 2017 were in patients with asthma [24]. Data from the 2021 North American survey indicated that 50 percent (105 of 209) of reported grade 3 or 4 nonfatal anaphylactic systemic allergic reactions occurred in patients with severe asthma [19]. The majority of patients with baseline forced expiratory volume in one second <70 percent of predicted experienced worsening bronchospasm after allergen injections in a prospective study of rush SCIT with a standardized Dermatophagoides pteronyssinus extract, demonstrating that severe airway obstruction is a risk factor for systemic reactions with SCIT [33].

Prior systemic allergic reactions — Patients who had systemic reactions to SCIT were more likely to have experienced prior large local reactions or previous injection-related systemic reactions [6]. The significance of large local reactions is discussed in more detail below. (See 'Dose adjustment for large local reactions' below.)

Dosing errors — Dosing errors were reported in 17 percent of fatal reactions and 25 percent of near-fatal reactions [17,18]. A survey of 1717 allergists conducted to examine the rate of dosing errors found that incorrect dosing of SCIT was reported by 74 percent of responders [34]. Dosing errors were thought to have resulted in 83 systemic reactions that required hospital treatment and one death.

Other factors that may impact outcomes — Beta-adrenergic blockers and angiotensin-converting enzyme (ACE) inhibitors do not increase the risk of systemic reactions during SCIT, but they could impact the effectiveness of epinephrine or impair normal compensatory responses to hypotension during anaphylaxis, respectively.

Beta-adrenergic blockers — Concomitant treatment with beta-adrenergic blockers does not appear to increase the risk for systemic reactions to SCIT but could result in more protracted and difficult-to-treat anaphylaxis [35,36]. Most clinicians generally restrict beta-blockers among patients initiating SCIT. (See "Anaphylaxis: Emergency treatment", section on 'Situations requiring caution'.)

Concurrent administration of beta-blockers was implicated in 2 percent of fatal reactions, although their actual contribution to fatal outcomes was uncertain [16,17]. A single patient with a near-fatal reaction to SCIT, who was on a beta-blocker, promptly responded to epinephrine and did not require glucagon [18].

Beta-blockers are relatively but not absolutely contraindicated in patients receiving SCIT [3]. This is most relevant to patients who have both stinging insect allergy and cardiac disease and are unable to discontinue beta-blocker therapy. In these patients, the benefit of preventing life-threatening anaphylaxis from a Hymenoptera sting by treating with venom immunotherapy (VIT) outweighs the theoretical risk of concomitant beta-blockade in the event of a serious systemic reaction to SCIT [37].

ACE inhibitors — Angiotensin-converting enzyme (ACE) inhibitors impede the metabolism of vasoactive mediators, such as bradykinin, which are generated during anaphylaxis and contribute to the hypotension and hypovolemia seen in this disorder [38]. Concomitant treatment with ACE inhibitors has been associated with more severe systemic reactions during VIT [39-41]. However, there does not appear to be a correlation between ACE inhibitor therapy and a higher incidence of anaphylaxis, either during VIT or during other types of immunotherapy [29,42]. The American practice parameters suggest that in patients with indications for both VIT and ACE inhibitor therapy, alternatives to ACE inhibitors be used, if possible. If no equally effective alternative medication is available, the clinician should make an individualized decision about the use of ACE inhibitors, considering the risks and benefits for that patient, as well as the patient's preferences [3].

Angiotensin II receptor blockers have not been associated with more severe anaphylaxis [3].

Combination therapy with both ACE inhibitors and beta-blockers is common, and patients with venom anaphylaxis may be receiving both of these medications. The decision to continue one, both, or neither of these medications must be made on an individual basis, keeping in mind that uncontrolled cardiovascular disease is a risk factor for a poor outcome from anaphylaxis [3]. Issues of cardiovascular medications in patients requiring VIT are discussed separately. (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients requiring ACE inhibitors or beta-blockers'.)

MANAGEMENT ISSUES — Timely recognition of anaphylaxis and prompt treatment with epinephrine are critical to good outcomes [15]. This is consistent with reports of fatal anaphylaxis to foods, venoms, and drugs, in which epinephrine injection was often delayed or not given at all [43]. Patients not responding to therapy should be promptly transferred to the emergency department. (See "Anaphylaxis: Emergency treatment" and "Fatal anaphylaxis", section on 'Possible risk factors'.)

Available data suggest that favorable outcomes in patients with SCIT-induced systemic reactions were associated with the following (table 3) [15-18]:

Timely injection of epinephrine. Epinephrine was delayed or not administered in 6 percent of near-fatal reactions versus 30 percent of reported fatal reactions [18].

Administration of SCIT and management of subsequent anaphylactic events in an allergy/immunology specialist's office (93 percent of near-fatal reactions versus 59 percent of fatal reactions) versus a primary care clinician's office or a patient's home.

Waiting in the office for the recommended 30 minutes after injections (eg, 3 percent of near-fatal reactions versus 12 percent of fatal reactions left the clinic early).

Establishment of a patent airway when necessary. Attempts at intubation or establishment of an airway were delayed or unsuccessful in 40 percent of patients with fatal reactions [17].

PREVENTION — Practice parameters have been developed by a joint task force (American Academy of Allergy, Asthma, and Immunology and American College of Allergy, Asthma, and Immunology) to improve the safety of SCIT, which contain specific recommendations to prevent SCIT-related anaphylaxis [3]. Key recommendations are shown in the table (table 4).

Ensure asthma is controlled — The practice parameters recommend that SCIT should not be initiated in a patient with asthma until symptoms have been stabilized with pharmacotherapy (table 4) [3]. In addition, asthma control should be assessed routinely prior to each injection by asking the patient about the presence of recent respiratory symptoms and obtaining a measurement of lung function (eg, peak expiratory flow rate or forced expiratory volume in one second). SCIT injections should be withheld during periods when the patient's asthma is poorly controlled. (See 'Asthma' above.)

Severe asthma is a relative contraindication to the use of SCIT, as is significant cardiovascular disease or any other severe medical conditions that could reduce the individual's ability to survive a systemic allergic reaction. In the North American surveys, allergists who never initiated SCIT in patients with uncontrolled asthma reported significantly fewer grade 3 and 4 systemic reactions [7].

Optimize safety — SCIT should only be administered in a medically supervised setting. Clinics in which SCIT is administered must have protocols, medications, supplies, equipment, and trained staff in place to manage life-threatening anaphylaxis [3]. Procedures should be established in the clinic to optimize the chance that patients who develop systemic reactions are treated promptly and correctly. Whenever possible, SCIT should be administered in an allergy/immunology specialist's office.

A 30-minute clinic observation period after injections is recommended, based on the finding that nearly all severe anaphylactic episodes begin within the first 30 minutes. As mentioned, requiring patients to check out with clinic staff before leaving may reduce risk of systemic allergic reactions [19]. (See 'Timing' above.)

SCIT should be administered in a setting where personnel are specially trained to detect the earliest signs and symptoms of systemic reactions and treat them promptly with epinephrine. Home administration of SCIT injections is not recommended.

Premedication — Many allergists advise patients to premedicate before each injection visit with a nonsedating H1 antihistamine, and some guidelines endorse this practice [44]. There is some evidence that this practice reduces the incidence of both local and systemic reactions [45-48]:

In a randomized study of 134 patients, fexofenadine 60 mg pretreatment given two hours prior to injections prevented severe systemic reactions, defined as asthma exacerbations or anaphylaxis, in patients receiving tree pollen and/or dust mite SCIT [45]. The incidence of severe systemic reactions was significantly lower in patients treated with fexofenadine versus placebo (0 versus 9 percent).

Pretreatment with an H1 antihistamine, such as levocetirizine 5 mg or terfenadine (no longer available), was also effective in reducing the rate of systemic reactions as well as local reactions in two trials of rush Hymenoptera venom immunotherapy (VIT) [46,47].

However, most of these studies were performed with aluminum hydroxide-adsorbed extracts or with rush venom protocols, both of which may confer lower risks of systemic reactions compared with aqueous extracts used more commonly in the United States, and evidence is lacking that pretreatment with H1 antihistamines can prevent near-fatal or fatal systemic reactions. In addition, some clinicians worry that antihistamines could mask early, milder symptoms of a systemic reaction, leading to delayed recognition and possibly progression to more severe symptoms, although data supporting this concern are lacking. The author's approach is to always premedicate patients undergoing accelerated buildup (ie, cluster) and not to insist that all patients premedicate during slow buildup or prior to maintenance injections.

The utility of other agents, such as H2 antihistamines, montelukast or zafirlukast, and glucocorticoids, as premedications prior to routine SCIT injections has not been extensively studied. Most allergists do not administer these as premedications with routine injections, with the exception of clinics performing accelerated cluster build-up protocols. In such accelerated protocols, patients are pretreated with either an H1 antihistamine alone (eg, loratadine) or combined pretreatment regimens (eg, oral prednisone plus montelukast plus an H1 antihistamine) prior to each session of multiple injections [13]. (See "Subcutaneous aeroallergen immunotherapy: Accelerated schedules (cluster and rush)".)

In general, premedication reduces the risk of systemic reactions versus no premedication during accelerated build-up with venom or aeroallergen extracts [49].

Omalizumab has been used to reduce the rate of systemic reactions in patients who require VIT but have had systemic reactions in response to the injections, including patients with mast cell disorders. This is discussed elsewhere. (See "Hymenoptera venom immunotherapy: Technical issues, protocols, adverse effects, and monitoring", section on 'Recurrent systemic reactions'.)

Prevention of dosing errors — Measures to reduce dosing errors included the following [17,18]:

Education of the staff preparing and administering SCIT injections.

Use of patient-specific vials that are clearly labeled.

Use of standard forms and protocols, including those recommended in the allergen immunotherapy practice parameters (see "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring", section on 'Total duration of therapy').

Performance of multiple identity checks (eg, name, date of birth) on each patient prior to each injection.

Avoidance of distractions to staff administering SCIT (eg, allow only one patient in the "shot room" at a time).

Caution in patients with previous systemic reactions — Previous systemic reactions are a major risk factor for fatal reactions and near-fatal reactions [27] (see 'Prior systemic allergic reactions' above). Recommendations for management of patients who experience systemic reactions include the following:

Discontinue SCIT or, if the decision is made to continue SCIT, adjust the allergen dose(s) for the subsequent injection(s).

Administer subsequent injections in the allergy/immunology specialist's office where the SCIT extracts were ordered and/or prepared and observe for longer than 30 minutes in patients with late-onset systemic reactions [3].

If SCIT is continued in those who experienced late-onset systemic reactions >30 minutes postinjection, consider training patients on the self-administration of epinephrine in the event of a future late systemic reaction [3]. It is concerning that only a minority of patients (≤26 percent) with delayed-onset grade 3 and 4 systemic reactions actually self-administered epinephrine during these events [24].

Epinephrine autoinjectors for higher-risk patients — For patients at heightened risk for systemic reactions, such as those with a prior systemic reaction to SCIT, a late-onset systemic reaction, or moderate to severe asthma, prescription and training on use of self-injectable epinephrine may be prudent.

Areas of uncertainty — Two areas of uncertainty in SCIT administration are the utility of adjusting doses of pollen extracts during peak pollen seasons and the utility of adjusting dosing in response to large local reactions.

Pollen SCIT in peak seasons — Systemic reactions occurred more commonly during peak pollen seasons in some studies [16-18]. However, two large studies including over 600,000 injections did not find a correlation between pollen counts and systemic reactions, although there was a correlation in one study with mean monthly mold counts from August to October [50,51]. Thus, there are several areas of uncertainty regarding best practices for managing pollen-allergic patients receiving SCIT during peak seasons.

Published data on the issue of dose adjustments for peak pollen seasons are limited, and clinicians differ in their approach. Several variables may be involved. In parts of the world where pollen exposure occurs year round, it may not be necessary to reduce the dose of the related aeroallergen during peak season, whereas this may be important in areas where pollen seasons begin more suddenly. In addition, the individual patient's sensitivity to pollen and whether or not the patient has concomitant asthma or past history of anaphylaxis to immunotherapy should be considered.

It is the author's practice to make adjustments to SCIT in response to peak pollen seasons on an individual basis. When doses are reduced, a typical adjustment for a patient on a maintenance injection (of 0.5 mL volume) would be 0.3 to 0.15 mL, which is then increased again when the pollen season is ending.

Some allergy experts empirically reduce maintenance doses during peak pollen seasons. In the surveillance study mentioned previously, practices that always reduced maintenance doses during peak pollen seasons were significantly less likely to experience moderate (grade 2) or severe (grade 3) systemic reactions, compared with those practices who often, sometimes, or never adjusted doses [25]. However, this could also reflect other preventive measures taken by those practices.

For patients who are in the build-up phase of SCIT, most clinicians increase doses of pollen SCIT normally during peak pollen season. Again, studies specifically addressing the safety of this practice are lacking, and clinicians should use clinical judgement if a patient is highly pollen allergic and experiencing significant symptoms.

Dose adjustment for large local reactions — Large local reactions do not appear to be harbingers of impending systemic reactions, but they may be markers of patients who are more likely to develop systemic reactions at some point during immunotherapy. This is reviewed in more detail elsewhere. (See "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring", section on 'Relationship between local and systemic reactions'.)

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: Anaphylaxis" and "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)

SUMMARY AND RECOMMENDATIONS

Incidence of systemic reactions to SCIT – The incidence of systemic reactions to subcutaneous allergen immunotherapy (SCIT) varies according to potency of allergens, modes of allergen preparation and modification, and allergen dosing protocols (eg, cluster or rush versus slow build-up regimens). Rates of systemic reactions in studies of SCIT with aqueous unmodified allergens using conventional build-up regimens with multiple allergens range from 0.1 to 0.6 percent of injections. (See 'Frequency' above.)

Fatalities and near-fatalities are rare – Fatal reactions are estimated to occur once in every 7.2 million injections and near-fatal reactions once in every 160,000 injection visits. (See 'Fatal and near-fatal reactions' above.)

Most reactions occur within 30 minutes – Most serious reactions begin within 30 minutes after administration of injections. Hypotension, upper airway obstruction, and bronchospasm are common in both near-fatal reactions and fatal reactions. Cutaneous manifestations (urticaria, angioedema, and pruritus) may be absent in fatal reactions, and their absence potentially delays recognition of a reaction. Rare delayed and biphasic reactions are possible. (See 'Clinical characteristics' above.)

Possible risk factors for severe reactions – Possible contributing factors for fatal reactions include uncontrolled asthma, history of previous systemic reactions, delayed treatment with epinephrine, dosing/injection errors, and administration of pollen SCIT during the peak pollen season. (See 'Factors associated with fatal and near-fatal anaphylaxis' above.)

Beta-blockers and ACE inhibitors – The contribution of concurrent beta-adrenergic blocker treatment to fatal outcomes is uncertain. Beta-blocker therapy is relatively contraindicated but may be necessary in patients with cardiovascular disease who also have insect sting anaphylactic reactions. Angiotensin-converting enzyme (ACE) inhibitors have been associated with more severe systemic reactions in patients receiving venom immunotherapy. (See 'Beta-adrenergic blockers' above and 'ACE inhibitors' above.)

Prompt recognition of systemic reactions and treatment with epinephrine – Timely detection of anaphylaxis and prompt injection of epinephrine are critical to good outcomes. SCIT should be administered in a setting where personnel are specially trained to recognize and manage anaphylactic reactions. Whenever possible, SCIT should be administered in an allergy/immunology specialist's office. (See 'Management issues' above and 'Timing' above.)

Supply higher-risk patients with epinephrine – Targeted prescription and training in the use of self-injectable epinephrine is prudent in patients at heightened risk for systemic reactions (ie, late-onset reactions, prior history of systemic reactions, history of moderate or severe asthma).

Caution with asthma – Patients with asthma who are receiving SCIT should be screened before each visit for injection(s) to determine if their asthma is well controlled. We recommend withholding injections during periods when the patient's asthma is poorly controlled and avoiding the initiation of SCIT in those patients with uncontrolled asthma (Grade 1B). (See 'Clinical characteristics' above and 'Factors associated with fatal and near-fatal anaphylaxis' above.)

Post-injection observation – We suggest that all patients receiving SCIT wait in the office for a minimum of 30 minutes after administration of the injection(s) (Grade 2C). Patients should be required to check out with office staff before leaving the clinic. (See 'Management issues' above and 'Timing' above.)

  1. Cooke RA, Vander-Veer A Jr. Human sensitization. J Immunol 1916; 1:201.
  2. CSM Update: Desensitising vaccines. Br Med J (Clin Res Ed) 1986; 293:948.
  3. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011; 127:S1.
  4. Cox L. Accelerated immunotherapy schedules: review of efficacy and safety. Ann Allergy Asthma Immunol 2006; 97:126.
  5. Greenberg MA, Kaufman CR, Gonzalez GE, et al. Late and immediate systemic-allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol 1986; 77:865.
  6. Roy SR, Sigmon JR, Olivier J, et al. Increased frequency of large local reactions among systemic reactors during subcutaneous allergen immunotherapy. Ann Allergy Asthma Immunol 2007; 99:82.
  7. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Risk factors for fatal and nonfatal reactions to subcutaneous immunotherapy: National surveillance study on allergen immunotherapy (2008-2013). Ann Allergy Asthma Immunol 2016; 116:354.
  8. Casanovas M, Sastre J, Fernández-Nieto M, et al. Double-blind study of tolerability and antibody production of unmodified and chemically modified allergen vaccines of Phleum pratense. Clin Exp Allergy 2005; 35:1377.
  9. Casanovas M, Martín R, Jiménez C, et al. Safety of immunotherapy with therapeutic vaccines containing depigmented and polymerized allergen extracts. Clin Exp Allergy 2007; 37:434.
  10. Nettis E, Giordano D, Pannofino A, et al. Safety of inhalant allergen immunotherapy with mass units-standardized extracts. Clin Exp Allergy 2002; 32:1745.
  11. Mellerup MT, Hahn GW, Poulsen LK, Malling H. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment. Clin Exp Allergy 2000; 30:1423.
  12. Harvey SM, Laurie S, Hilton K, Khan DA. Safety of rush immunotherapy to multiple aeroallergens in an adult population. Ann Allergy Asthma Immunol 2004; 92:414.
  13. Winslow AW, Turbyville JC, Sublett JW, et al. Comparison of systemic reactions in rush, cluster, and standard-build aeroallergen immunotherapy. Ann Allergy Asthma Immunol 2016; 117:542.
  14. Rezvani M, Bernstein DI. Anaphylactic reactions during immunotherapy. Immunol Allergy Clin North Am 2007; 27:295.
  15. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987; 79:660.
  16. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Survey of fatalities from skin testing and immunotherapy 1985-1989. J Allergy Clin Immunol 1993; 92:6.
  17. Bernstein DI, Wanner M, Borish L, et al. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol 2004; 113:1129.
  18. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol 2006; 117:169.
  19. Epstein TG, Murphy-Berendts K, Liss GM, Bernstein DI. Risk factors for fatal and nonfatal reactions to immunotherapy (2008-2018): postinjection monitoring and severe asthma. Ann Allergy Asthma Immunol 2021; 127:64.
  20. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol 2010; 125:569.
  21. Winther L, Arnved J, Malling HJ, et al. Side-effects of allergen-specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy 2006; 36:254.
  22. Bernstein DI, Epstein T, Murphy-Berendts K, Liss GM. Surveillance of systemic reactions to subcutaneous immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI collaborative study. Ann Allergy Asthma Immunol 2010; 104:530.
  23. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions? Ann Allergy Asthma Immunol 2013; 110:274.
  24. Epstein TG, Liss GM, Berendts KM, Bernstein DI. AAAAI/ACAAI Subcutaneous Immunotherapy Surveillance Study (2013-2017): Fatalities, Infections, Delayed Reactions, and Use of Epinephrine Autoinjectors. J Allergy Clin Immunol Pract 2019; 7:1996.
  25. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Immediate and delayed-onset systemic reactions after subcutaneous immunotherapy injections: ACAAI/AAAAI surveillance study of subcutaneous immunotherapy: year 2. Ann Allergy Asthma Immunol 2011; 107:426.
  26. Liss GM, Murphy-Berendts K, Epstein T, Bernstein DI. Factors associated with severe versus mild immunotherapy-related systemic reactions: a case-referent study. J Allergy Clin Immunol 2011; 127:1298.
  27. Bernstein DI, Epstein TEG. Safety of allergen immunotherapy in North America from 2008-2017: Lessons learned from the ACAAI/AAAAI National Surveillance Study of adverse reactions to allergen immunotherapy. Allergy Asthma Proc 2020; 41:108.
  28. Greenberg MA, Kaufman CR, Gonzalez GE, et al. Late systemic-allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol 1988; 82:287.
  29. Rank MA, Oslie CL, Krogman JL, et al. Allergen immunotherapy safety: characterizing systemic reactions and identifying risk factors. Allergy Asthma Proc 2008; 29:400.
  30. Dursun AB, Sin BA, Oner F, Misirligil Z. The safety of allergen immunotherapy (IT) in Turkey. J Investig Allergol Clin Immunol 2006; 16:123.
  31. Scranton SE, Gonzalez EG, Waibel KH. Incidence and characteristics of biphasic reactions after allergen immunotherapy. J Allergy Clin Immunol 2009; 123:493.
  32. Confino-Cohen R, Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Ann Allergy Asthma Immunol 2010; 104:73.
  33. Hejjaoui A, Dhivert H, Michel FB, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy schedule. J Allergy Clin Immunol 1990; 85:473.
  34. Aaronson DW, Gandhi TK. Incorrect allergy injections: allergists' experiences and recommendations for prevention. J Allergy Clin Immunol 2004; 113:1117.
  35. Hepner MJ, Ownby DR, Anderson JA, et al. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol 1990; 86:407.
  36. Lang DM. Do beta-blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy Asthma Rep 2008; 8:37.
  37. Müller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hymenoptera venom allergy. J Allergy Clin Immunol 2005; 115:606.
  38. Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physiologic manifestations of human anaphylaxis. J Clin Invest 1980; 66:1072.
  39. Tunon-de-Lara JM, Villanueva P, Marcos M, Taytard A. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. Lancet 1992; 340:908.
  40. Ober AI, MacLean JA, Hannaway PJ. Life-threatening anaphylaxis to venom immunotherapy in a patient taking an angiotensin-converting enzyme inhibitor. J Allergy Clin Immunol 2003; 112:1008.
  41. Ruëff F, Przybilla B, Biló MB, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: importance of baseline serum tryptase-a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. J Allergy Clin Immunol 2009; 124:1047.
  42. White KM, England RW. Safety of angiotensin-converting enzyme inhibitors while receiving venom immunotherapy. Ann Allergy Asthma Immunol 2008; 101:426.
  43. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30:1144.
  44. Roberts G, Pfaar O, Akdis CA, et al. EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy 2018; 73:765.
  45. Ohashi Y, Nakai Y, Murata K. Effect of pretreatment with fexofenadine on the safety of immunotherapy in patients with allergic rhinitis. Ann Allergy Asthma Immunol 2006; 96:600.
  46. Müller UR, Jutel M, Reimers A, et al. Clinical and immunologic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy. J Allergy Clin Immunol 2008; 122:1001.
  47. Brockow K, Kiehn M, Riethmüller C, et al. Efficacy of antihistamine pretreatment in the prevention of adverse reactions to Hymenoptera immunotherapy: a prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 1997; 100:458.
  48. Nielsen L, Johnsen CR, Mosbech H, et al. Antihistamine premedication in specific cluster immunotherapy: a double-blind, placebo-controlled study. J Allergy Clin Immunol 1996; 97:1207.
  49. Calabria CW. Accelerated immunotherapy schedules. Curr Allergy Asthma Rep 2013; 13:389.
  50. Tinkelman DG, Cole WQ 3rd, Tunno J. Immunotherapy: a one-year prospective study to evaluate risk factors of systemic reactions. J Allergy Clin Immunol 1995; 95:8.
  51. Lin MS, Tanner E, Lynn J, Friday GA Jr. Nonfatal systemic allergic reactions induced by skin testing and immunotherapy. Ann Allergy 1993; 71:557.
Topic 394 Version 25.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟