Chinese Guideline on Allergen Immunotherapy for Allergic Rhinitis: The 2022 Update

AR prevalence

AR is a highly prevalent chronic disease, affecting 40% of the global population.1 In China, it constitutes a huge economic burden of 51.28 billion EUR per year.2 Additionally, an unexpectedly high prevalence of epidemiologic AR (18.6%–52.9%) and pollen-induced AR (PiAR, 10.5%–31.4%) were reported in 6 cities in the northern grasslands.3 The prevalence of PiAR in urban areas (23.1%) was significantly higher than in rural areas (14.0%).3 Unlike data for adults, most epidemiological studies on AR in children are limited to municipal or provincial administrative regions in the last 5 years (2016–2021). Recently published studies have indicated the prevalence of self-reported AR (28.6%) among children aged 6–12 years in Wuhan and physician-diagnosed AR in 0- to 17-year-olds (14.4%).4, 5 Interestingly, in most Chinese cities, 45% of AR outpatient visits occurred in August and September,6 which could be attributed to the multi-sensitization and co-exposure to dust mites and some autumn allergens during this period. This inference was further supported by a recent study that listed HDM, Artemisia, Humulus Japonicus, Alternaria alternata, and Cladosporium herbarium allergens, as the 5 most common aeroallergens in China.7

Air pollution and AR

Similar to other allergic diseases, AR results from genetic and environmental factors. In recent years, due to rapid socio-economic development and continuous ecological degradation, air pollution is becoming a serious threat to human health. Air pollutants related to allergic diseases include particulate matter (PM), nitrogen oxides (NO_x), sulfur dioxide (SO₂), carbonic oxide (CO), ozone (O₃), and environmental tobacco smoke. Among them, PM ≤ 2.5 μm (PM2.5) in aerodynamic diameter can deposit in the alveoli, enter the circulatory system through the respiratory barrier, and spread to the whole body, triggering numerous allergic diseases. In vitro and animal studies have shown that air pollutants and allergens may have synergistic adverse effects during the development of allergic respiratory diseases.8, 9

An increasing number of epidemiological studies have shown that air pollution is a risk factor for AR. Aerial PM concentration is related to the incidence of AR outpatients.10, 11, 12 Chu et al. 12 reported that the interquartile range in PM10 (difference of estimates, 5.86%; 95% confidence interval [CI], 3.00–8.81; P = 4.72 × 10⁻⁵) and PM2.5 (difference of estimates, 5.39%; 95% CI, 2.73–8.12; P = 5.67 × 10⁻⁵) concentrations were positively associated with the number of AR patients, with 3-day cumulative effects in a single-pollutant model. Additionally, PM2.5 induces substantial goblet cell hyperplasia, collagen deposition, eosinophil production, and immunoglobulin E (IgE) protein expression; moreover, PM2.5 exacerbates the symptoms of AR in animal models.13, 14, 15 The role of other air pollutants on the incidence and severity of AR has also been examined. Sun et al.16 reported that O₃ increases sneezing frequency and the expression of type 2 T-helper (Th2) cytokines, including interleukin (IL)-5, IL-13, and eotaxin. Additionally, SO₂ and NO_x levels have been reported to correlate with the daily number of AR patients.17

However, it is not clear whether air pollution can cause allergic diseases de novo. Birth cohort studies have inconsistent results when comprehensively examined the relationship between early childhood exposure to air pollutants and the development of AR, asthma, and other allergic diseases. A systematic review and meta-analysis of birth cohort studies shows a significant association between early childhood PM2.5 exposure and sensitization to outdoor but not indoor aeroallergens.18 Based on 5 European birth cohort studies, Gruzieva et al.19 reported no clear association of PM2.5 or PM10 exposure with allergic sensitization in children aged ≤ 10 years.

Inhaled allergens pattern

Since avoiding allergen exposure is key to AR management, identification of allergens is crucial for the diagnosis and treatment of AR. The spectra of inhaled allergens in China are similar to those of Western countries. HDMs, pollen, fungus, animal dander, and cockroaches are the most common aeroallergens,20, 21 among which the 3 most prevalent are from the species Dermatophagoides pteronyssinus (Der p), Dermatophagoides farinae (Der f), and Artemisia. 21

HDMs are the major cause of AR in China, especially in Southern China.22, 23, 24, 25, 26 Chen et al.22 generated a distribution map of HDMs and found that the rate and the regional distribution patterns of both Der p and Der f sensitization were similar in AR patients. Der p and Der f were the highest in the southern and central parts of China and the lowest in the northern regions, especially in the northwest. Yang et al. 25 demonstrated that Der p components Der p 1 and Der p 2 could induce Der p sensitization in Central China.

Due to high seasonal pollen exposure, which is primarily influenced by local environmental and climate conditions, the prevalence of PiAR is extremely high in Northern China. Most patients with PiAR are sensitive to ≥2 pollens, of which Artemisia, Chenopodium, and Humulus scandens are the most common.3 In the northern area of the Yangtze River, Artemisia pollen is the most allergenic.27 In Northwest China, the three most prevalent aeroallergens were mugwort, ragweed, and dandelion pollen.23 Interestingly, there was an increase in pet allergen sensitization from 2005 to 2014.26 In children, Der p was the most common allergen, and the proportion of children with high levels of allergen-specific IgE (sIgE) against Der p increased with age.28 A broader spectrum of allergen sensitization was more common in children than in adults.21

Desensitization effects following AIT

Both early and late phase allergic responses are suppressed after AIT, starting with the late phase response 2 weeks after commencement of treatment. Most patients start to acquire tolerance against late-phase skin response during the very early phase following AIT.31 A key mechanistic feature of the early phase reactions is IgE-dependent mast cell and basophil degranulation. High-affinity IgE receptors preferentially bind to free IgE molecules, whereas IgE–allergen immune complexes are cleared upon binding to the low-affinity receptor CD23 on B cells.

Modulation of antigen-presenting cell function following AIT

The second stage in the response is the generation of allergen-specific Tregs and Bregs as well as the suppression of allergen-specific Th2 cells and type 2 innate lymphoid cells.32 The tolerogenic activity of DCs depends on the maturation status and activation of the cell, in addition to the cell lineage (e.g., myeloid vs. plasmacytoid DCs [pDCs]), all of which can be influenced by immunomodulatory agents. In the absence of pro-inflammatory signals during AIT, airway DCs possess an intermediate phenotype (between immature and mature), expressing a range of co-stimulatory molecules resulting in tolerogenic interaction with lymph-node T cells. Depletion and adoptive transfer of pulmonary pDCs in an asthmatic mouse model showed that pDCs play a central role in protection against sensitization to allergens and the development of asthma.33

Modulation of T-cell responses and peripheral T-cell tolerance to allergens following AIT

Active regulation might be an essential mechanism for inducing and maintaining peripheral tolerance to allergens. In allergic diseases, the activities of CD4⁺Foxp3⁺ Tregs, CD4⁺Foxp3^- type 1 Tregs (Tr1), and IL-35-inducible Tregs (iTR35) are compromised, and an abnormal Th2 response is observed. However, these abnormal immune responses can be ameliorated by AIT.34, 35 Studies show that Treg and Th1/Th2 responses are normalized during AIT and that there is an upregulation of allergen-specific Tregs and improved clinical response. Moreover, a decrease in the activity and proliferation of allergen-specific follicular helper T cells (Tfh), which contributes to sIgE production, and an increase in follicular regulatory T cells (rTfh) in patients with AR is observed after AIT.36, 37, 38

Modulation of antibody responses following AIT

B-cell responses, including the induction of IL-10⁺ regulatory B cells (Bregs) and the production of IgG4-associated blocking antibodies, are observed after successful AIT. Although allergen-specific antibody responses in healthy control individuals are often undetectable, exposure to high concentrations of allergen can elevate serum levels of allergen-specific IgG4, IgG1, and IgA, but not IgE.39 Der-p-specific IgG (sIgG), sF(ab’)2, and sFab antibodies markedly blocked Der-p-allergen sIgE complex binding to B cells, inhibited basophil activation, and reduced the production of IL-5, IL-13, IL-17, and tumor necrosis factor-α.40 Indeed, there is sufficient evidence that functional activity, rather than quantity of IgG antibodies, might be a more appropriate measure of AIT efficacy.

Most recently, a fraction of antigen-specific CD38⁺ B cells was detected in AR patients.41 A negative correlation was demonstrated between CD38⁺ B cell frequency and Treg frequency in AR patients treated with AIT. Exposure to specific antigens induced CD38⁺ B cells to produce IL-6, which converted Tregs to Th17 cells. Additionally, an increased number of circulating allergen-specific memory B cells and IL-1RA production by Bregs was observed after long-term AIT.

In summary, both innate and adaptive immune responses that contribute to allergic inflammation are suppressed by AIT. Successful AIT is associated with suppression of allergic inflammatory cells and normalization of the Th1/Th2 response. The immunologic tolerant state following AIT is associated with the induction of distinct phenotypes of Tregs and Bregs (Fig. 1). Insight into the mechanisms of AIT has allowed identification of novel therapeutic strategies for more effective and safer AIT.

Fig. 1
Mechanisms of immunotherapy.
IL, interleukin; TGF, transforming growth factor; Ig, immunoglobulin.

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ILIT

Based on the “geographic concept of immunogenicity,” ILIT directly delivers the allergen to B and T cells in the lymph nodes and is reported to induce a more robust cytotoxic T-cell response than other routes.54 The inguinal lymph nodes are the most common injection sites for ILITs.55, 56 Considering the inconvenience of inguinal ILIT injection, Wang et al.55 conducted a first-in-human cervical ILIT study. No moderate–severe AEs were observed. The advantages of ILIT over conventional treatments are the shorter treatment duration and fewer injections. The current protocols for ILIT suggest 3 injections at 4-week intervals, which could be completed over 8 weeks.55, 57, 58, 59, 60, 61, 62, 63 Beyond convenience, ILIT has shown promising safety and tolerance. Senti et al. 57 compared ILIT with SCIT (n = 58 vs. n = 54) and demonstrated that ILIT had fewer AEs. The pain of intralymphatic injection was reported as the most frequent AE.64 Park et al. 65 further compared the injection pain of ILIT with venous punctures during blood sampling. They reported that the pain caused by intralymphatic allergen injection was more intense (VAS score: 3.5 ± 2.0 vs. 2.8 ± 1.7 mm, P = 0.019), but not different from that of intralymphatic placebo injection. Sixteen studies (14 RCT55, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70 and 2 cohort studies61, 71) provided data on anaphylaxis and death; among the 1,454 injections, 4 anaphylaxis events and no deaths were reported.

Efficacy evaluations of ILIT have shown inconsistent results, possibly due to the variation in allergen extracts, dosages, and administration intervals. Some studies showed no clinical benefit of ILIT for perennial AR.55, 58, 61 However, Park et al.65 reported that ILIT reduced daily medication use and skin reactivity to HDM and cat allergens 4 months after treatment. For seasonal AR, a meta-analysis showed short-term (< 24 weeks) benefits on CSMS in the 4-week, but not the 2-week, injection interval subgroup.54 The medium-term (24–52 weeks) benefits of seasonal AR symptom VAS scores favored ILIT when analyzing data from 4 RCTs (mean difference, 1.93; 95% CI, 0.92–2.94; P < 0.01).54 Skaarup et al.66 reported no long-term (> 52 weeks) effect of ILIT on CSMS compared with placebo; Terada et al.67 also found no long-term effect of ILIT using VAS scores for the evaluation of clinical benefit. The dosages were fixed in most studies, whereas 3 used escalating doses.58, 60, 70

ILIT requires only 3 injections over 8 weeks, and the cumulative dose is 1/1,000 of a 3-year SCIT. Compared to the conventional AIT routes, ILIT is quicker and reduces the number of clinical visits and costs. Importantly, although the safety and tolerability of ILITs is proven, the effectiveness of ILIT should not be overstated due to the discordance in efficacy evaluations. No recommended dose could be concluded from the published studies and escalating dosages may increase the risk of anaphylactic reactions.70 A preseason booster dose was assessed in 3 studies, Konradsen et al.63 and Weinfeld et al. 71 showed clinical improvement, whereas Skaarup et al.66 reported no additional effects of the preseason booster. Dose-range studies regarding effectiveness using established allergens (grass pollen, birch pollen, and mountain cedar pollen) and studies with a larger sample size, consistent efficacy indicators, and long-term follow-up periods are needed.

EPIT

EPIT delivers allergens via repeated applications to the skin, targeting epidermal Langerhans cells; it can reduce both local and systemic AEs. First used over a century ago, the disruption of the skin has evolved from “skin scarification” to the commonly used “tape stripping.”72 Although the tape-stripping method increased the penetration of allergens into the epidermis, it provoked similar Th2 immune responses and allergic sensitization to scarification.73 Senti et al.74 conducted 3 studies with grass pollen applied on patches after repeatedly tape-stripping the skin. Six patches were given preseason at weekly intervals and self-applied onto the tape-stripped skin of 98 subjects. EPIT produced a median symptom improvement of 48% after treatment and 40% in the treatment-free follow-up year compared to a 10% and 15% improvement after placebo EPIT, respectively (allergen extract: n = 48; placebo: n = 50, P = 0.003). Furthermore, sIgG4 responses were significantly elevated (P < 0.001) in the allergen EPIT group, but not in the placebo group. One systemic reaction (SR) was reported by a patient after tape stripping, but before application of the patch. Local side effects were associated with the duration of patch administration. EPIT efficacy was dose-dependent, and a high dose was associated with local skin inflammation.75

Several innovative epidermal powder delivery systems are understudied, including electronic spreading (Viaskin™), laser-based microporation, and microneedle arrays.76 Powder-laden dissolvable microneedle array (PLD-MNA) is reported to have a higher powder delivery rate than Viaskin. Additionally, various lyophilized extracts of allergens that are available for skin prick tests (SPTs) can also be directly loaded into PLD-MNAs. PLD-MNAs should be used in clinical trials. Future investigations into EPITs seem promising.

IDIT

Slovick et al.77 reported in 2017 that IDIT with the major timothy allergen, Phl-p 5, was associated with worse nasal and asthma symptoms during the grass pollen season, although it did reduce allergen-specific late-phase cutaneous reactions compared with the histamine control. IDIT also increased Phl-p-5-specific serum IgE and led to higher expression of Th2 and lower expression of Th1 on the surface of T cells cultured from skin biopsy specimens. A multicenter, placebo-controlled RCT study in Spain confirmed that in patients with grass PiAR, IDIT with glutaraldehyde-polymerized Phleum pratense was effective and safe. During the pollen season for 2 consecutive years, 6 injections/year were administered. In the second pollen season, the level of sIgE was decreased whereas IgG4 was comparable to baseline.78 Skillful medical workers are required to administer IDIT.

In summary, using novel routes of administration has dramatically reduced the number of treatments required compared to conventional AIT. Although the safety and tolerability of these novel routes were acceptable, only ILIT and EPIT seem promising in terms of efficacy. Even then, this effectiveness is only shown for seasonal AR patients. Considering the comparatively limited number of patients in ILIT clinical trials, the efficacy and safety of ILIT need confirmation. Further dose-range studies, especially with allergens beyond seasonal pollen, are also required.

SPTs

SPTs are widely used for rapid detection of IgE-mediated allergic reactions in vivo because of their simplicity, sensitivity, and low cost. They demonstrate high sensitivity and specificity during the diagnosis of inhalant allergens.100

Importantly, SPTs should be standardized, and operators should receive pre-job training and obtain qualifying certifications. Standardized allergen extracts (prick fluid), negative control (saline/glycerin), and positive control (5–10 mg/mL histamine solution) are required for SPTs. Wheal or erythema is measured approximately 15–20 minutes after pricking the extracts into the skin in patients and 20 minutes to 24 hours, in patients with delayed skin reactions. Unilateral or bilateral forearms are routinely used for the test, but the back can also be used, especially in infants. Wheal diameters ≥ 3 mm are considered a positive reaction,101 and the red blush can be used as a reference. Metal single-point pricks are recommended in SPTs,102 and the skin index (SI) is often used to assess SPT results. The SI is the ratio of average diameter of wheal to positive control, and determined according to 4 grades: +, 0.3 ≤ SI < 0.5; ++, 0.5 ≤ SI < 1.0; +++, 1.0 ≤ SI < 2.0; and ++++, SI ≥ 2.0.

Clinical studies show that the 8 most common types of aeroallergen cover 95%–99% of allergic patients.103 Since the only NMPA-approved allergens in China are from HDMs, the clinical application of SPTs in China is greatly restricted.

SPTs can be performed in infancy, but the responsiveness is very low.104 However, children’s responsiveness to SPTs increases with age and continues until adulthood before gradually declining.105

Notably, it is important to consider the patient’s clinical symptoms and medication history when interpreting SPTs results. False-positive skin tests can result from dermographism or a nonspecific enhancement from a nearby strong positive reaction. False-negative skin tests may be caused by poor potency extracts (reagent), modulation of allergic reactions by drugs, or inadequate prick force.106

Serum allergen sIgE tests

The primary purpose of an allergen test is to identify the causative allergens (usually allergen proteins) that cause allergic diseases. Since 1967,107 the serological allergen sIgE test has been regarded as an effective diagnostic method for human allergic disease. Serological sIgE tests are not as affected as SPTs by factors such as age, drug usage, and dermatographism, and are especially effective for false-negative SPT individuals. Qualitative, semi-quantitative, and quantitative IgE antibody immunoassays are currently available. The full-quantitative detection of physiological levels of total and sIgE is important for patient management and monitoring of therapeutic interventions, such as anti-IgE therapies. Quantitative system results are generally reported in international units (kU/L [serum total IgE assays] or kUA/L [serum sIgE antibody assays]).108 Historically, patients with sIgE concentrations ≥ 0.35 kUA/L were considered positive. However, recently it was proposed that IgE antibody tests d be reported as analytical results and not based on differential positive or negative thresholds. Additionally, it was proposed that the lower limit of quantitation for autoanalyzer-based IgE assays be 0.1 kUA/L.109 However, IgE antibody levels between 0.1 and 0.35 kUA/L must be cautiously interpreted by clinicians and should be combined with the actual symptoms after allergen exposure.110 This should be given considerable attention when the sIgE result is employed to distinguish between sensitization and allergy at all concentrations, i.e., an sIgE positive result alone, without allergic symptoms, is insufficient for a definitive diagnosis of allergy.

Nasal cytology is a simple, non-invasive, economical method of assessing pathological aspects of nasal mucosa.111, 112 It is a useful auxiliary method for the diagnosis and prognosis of AR. There are various techniques to obtain specimens for nasal cytology, such as nasal lavage, pre-weighted sinus packs, aspiration by micro-suction tubes, nasal brushing, nasal scraping, nasal swab, nasal smear, and nasal biopsy,112, 113 and this is followed by sample staining and microscopy. At least 50 fields should be evaluated at 1,000× magnification. The counts of epithelial cells, mucinous cells, lymphocytes, neutrophils, eosinophils, and mast cells can be expressed as a percentage of the total cells, an absolute quantity, or by a semi-quantitative grading.111, 112

Eosinophil number is regarded as an important marker for atopic reaction.114 In various studies, the nasal cytological examination of eosinophils appears to be an auxiliary diagnostic tool with moderate sensitivity and high specificity in AR diagnosis.115 Although a nasal cytological test of eosinophils is not necessary for the routine diagnosis of AR, it is often introduced as a useful differential diagnostic method for AR and other subtypes of non-allergic rhinitis in the clinic. Eosinophil or neutrophil dominated inflammation is reported if the ratio of eosinophils or neutrophils is more than 20% of the total inflammatory cells.112 Mast cell degranulation is graded as follows: 1, mild granules; 2, a moderate number of granules; 3, many granules; and 4, massive degranulation.112 Furthermore, eosinophilia correlates significantly with clinical parameters and nasal atopic reaction in AR patients.116 The cytological measurement of other cells, such as mast cells, basophils, neutrophils, goblet cells, and epithelial cells, may provide useful information for the differential diagnosis and management of AR. A study reported differences in the percentages of epithelial cells and neutrophils in the nasal cavity of perennial and intermittent AR patients.117 Moreover, a recent publication demonstrated that inhibiting neutrophil proliferation and activity is important in AR patients with high nasal neutrophil counts.113 Nasal cytology may have the potential to identify subtypes of AR for effective treatments.

Huggins and Brostoff118 demonstrated, for the first time, that sIgE could be detected in nasal secretions from AR patients. In a mouse model, prolonged low-dose allergen exposure in the sensitization phase could induce localized sIgE and prominent accumulation of eosinophils in nasal mucosa without detectable levels of serum sIgE.119 Several studies have since demonstrated local production of IgE antibodies in the nasal secretion and nasal mucosa of AR patients, leading to the concept of “entopy.”120 To date, local sIgE is used not only for endotype diagnosis of chronic rhinitis121 but also for precise diagnosis of AR. In a study involving 51 rhinitis patients, it was observed that the sIgE level in nasal secretions could be a reliable non-invasive alternative to serum sIgE for diagnosis.122 Additionally, a new type of rhinitis, local AR (LAR) was discovered using local sIgE, with a 7.7% prevalence in Southern China. Pollen was the most common sensitizing allergen for LAR among patients, differing from results in Caucasians where HDM was the dominant sensitizing allergen. Monosensitization was the predominant pattern in Chinese LAR patients.123 Additionally, the nasal allergen provocation test (NAPT) was reported as the most effective method for the diagnosis of LAR. However, NAPT has several limitations in clinical practice, including the absence of standardized methods and some reagents, the presence of several test protocols, the need for trained personnel, and difficulties in performing on pediatric patients. In a prospective single-center study involving 212 chronic rhinitis patients, local sIgE levels in nasal secretions were reliable and effective for diagnosing LAR (Fig. 2).124

Fig. 2
Stages for the diagnosis of different chronic rhinitis endotypes.
Ig, immunoglobulin; AR, allergic rhinitis; LAR, local allergic rhinitis; NARES, nonallergic rhinitis with eosinophilia syndrome; IR, idiopathic rhinitis; NAPT, nasal allergen provocation test.

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Indication and contraindication

Contraindications

The decision to use SCIT in patients with contraindications or concomitant diseases is usually based on the risk-benefit balance. In individual cases, SCIT may be a treatment option when the expected benefit is greater than the potential risk. This information is required by clinicians to determine whether patients have relevant absolute or relative contraindications, which could result in the risk of SCIT exceeding the expected benefits (Table 1).1, 130, 131, 132

Table 1
Contraindications to SCIT

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Special considerations in immunotherapy

HDM allergens are the most relevant allergens in AR during childhood.24 AIT is one of the most useful methods for treating respiratory diseases due to HDM allergy. AIT products are commercially available for SCIT or SLIT administration. Alternative routes, such as intralymphatic or epicutaneous administration, have not been tested in a pediatric population.132

Concerning AIT, children belong to a so-called special population. Age and safety are important factors for considering when initiating AIT in children. Although the clinical efficacy of AIT in AR is well established, children > 3 years old are seldom involved in clinical practice or trials. For safety reasons, it has been established by expert consensus that AIT can only be applied to children at ≥ 5 years old. However, AIT can be considered in children < 5 years old on an individual basis. Several factors should be considered, such as the impact on quality of life, expected acceptance, and adherence to the AIT. Attending physicians should communicate effectively with patients and their families regarding the practicalities, benefits, risks, and contraindications such as uncontrolled asthma.

In terms of indications, AIT is currently recommended in children with moderate-to-severe AR132 and should be initiated as early as possible for optimal results. Children with AR who are nonresponsive to standard pharmacotherapy should be considered for AIT.

Several published studies have examined the efficacy and safety of AIT.133, 134, 135, 136, 137 Moreover, evidence has shown that AIT could reduce symptoms and medication use. Additionally, a controlled trial of pollen immunotherapy in children suffering from seasonal AR revealed that significantly fewer SCIT-treated subjects had developed asthma at a 10-year follow-up.133 These studies provide evidence that SCIT may reduce the onset of new allergen sensitization in children.134, 135 Currently, there is modest evidence for the clinical efficacy of continuous SCIT in children suffering from seasonal AR to grass pollen and perennial AR to HDMs,136 and there is no evidence suggesting that AIT can worsen eczema or induce more frequent exacerbations. A comparative study of SCIT and SLIT showed that local AEs were reported in both SCIT- and SLIT-treated children, with similar numbers seen in the placebo group.136 In a recent large-scale study, a total of 19699 SCIT and 131550 SLIT doses were administered; the estimated frequency of systemic side effects with SCIT and SLIT was 0.11% and 0.004%, respectively, and the probability of abscission due to adverse reactions was similar between the two treatments.137 Overall, studies have shown that both SCIT and SLIT are safe and well-tolerated treatments in children with AR.

Currently available data suggest that AIT (SCIT and SLIT) should be used for at least 3 years in children to achieve significant clinical efficacy.132

AIT during pregnancy

AR constitutes a significant disease burden among women of childbearing age and pregnant women. AIT has also been considered for use during pregnancy. A review on the safety of AIT during pregnancy showed that there was no significant difference in maternal or fetal complications in pregnant women using AIT (both SCIT and SLIT to inhalant allergens) compared to the control group. Among some pregnant women (10/453 pregnancies) who experienced generalized reactions while receiving AIT, none were found to have fetal complications. Neither SCIT nor SLIT during pregnancy altered the risk of developing atopic disease in the offspring.138 According to the European Academy of Allergy and Clinical Immunology (EAACI), AIT may be continued during pregnancy139; however, data regarding the safety of continuing AIT during pregnancy is presently lacking in China. In China, before initiating AIT, it is usually verified if the patient has a plan for pregnancy in the near future. However, proper patient education is necessary for informing patients of the possible risks, benefits, and safety of AIT during pregnancy. Some data suggest that the initiation of AIT during pregnancy might be safe.140, 141 However, given the limitations of the medical environment in China, commencing AIT during pregnancy is not recommended.

Training of immunotherapy personnel

1. Due to the COVID-19 pandemic, there have been considerable changes in the procedure of AIT and its related medical risks. These changes emphasize the need for training SCIT managers in the post-pandemic era.142 However, the responsibilities of SCIT personnel during the pandemic are as follows.

2. To ensure the development and operation of SCIT during the pandemic, we recommend training medical personnel and patients. The training content for medical personnel should include the following:

Fig. 3
Risk levels of allergen-immunotherapy-related diagnosis and treatment activities during the pandemic. FeNO, fractional exhaled nitric oxide.

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3. Patient education and training are also an important part of the AIT process. To ensure effective and safe diagnosis, and effective AIT treatment during the pandemic, it is recommended that patient training include the following:

Table 2
Suggested intervals for vaccination during AIT

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Management and follow-up of patients

Treatment of AIT patients comprises that in-hospital and out-of-hospital managements. The former involves electronic or hard-copy medical records, whereas the latter mainly involves patient follow-up in the form of telephone calls and SMS messages. Patient follow-up includes education on allergic diseases and telephone reminders of treatment schedules.

Conventional immunotherapy

Presently, the only NMPA-approved SCIT vaccines in China are standardized allergen extracts of mite allergen, Novo Helisen-Depot (NHD) (Allergopharma GmbH & Co. KG, Germany; approved in 1999) and Mites allergens ALK (503) Der p (ALK-Abello A/S, Denmark; NMPA approved in 2004).7 Both vaccines are now widely used. There have been several studies on the long-term therapeutic effects of SCIT with standardized HDM allergens in AR patients in China.148, 149, 150, 151, 152 SCIT includes the initial and treatment phases. SCIT involves initial exposure to a diluted concentration of antigen as determined by the safe starting dose or the “end-point” from quantitative testing.153 This is followed by the escalation phase, in which the dose is gradually increased on a regular schedule to a therapeutic dose that treats symptoms without causing unacceptable reactions.154 The final phase is the maintenance phase, which is maintained for 3–5 years.

Maintenance schedules

The maximum tolerated dose at the initial stage is the maintenance dose, which is 100,000 standard quality (SQ) units, equivalent to Vial No. 4 (1 mL). After reaching the maintenance dose, the first injection is administered every 2 weeks; the second is administered 4 weeks later; and the third is administered 4–8 weeks after that (as determined by the clinicians). This is followed by subsequent administrations (Table 3). The maintenance dose is then injected every 4–8 weeks for 3–5 years.

Table 3
Conventional immunotherapy schedules

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Cluster schedules

Generally, SCIT is composed of 2 phases: a build-up phase and a maintenance phase.132 Conventional SCIT procedure consists of weekly injections for 15 weeks and maintenance injections every 4 or 8 weeks for 3 years.155 To improve long-term compliance and reduce the number of patient visits, cluster or rush schedules have been developed, which involve shortening the build-up phase by administering multiple injections at the same visit to reach the maintenance dose within a shorter time than the conventional schedule. However, the safety of this schedule is of considerable concern. A meta-analysis of 5 observational studies and 6 interventional studies demonstrated that the cluster schedule was safe for AR patients with or without asthma.156 Moreover, studies have shown that the cluster schedule contributes to more rapid symptomatic improvement (6 weeks earlier than with the conventional SCIT schedule), without increasing systemic adverse effects (0.15% of injections).155, 157 The most widely accepted cluster schedule targeting HDMs involves injecting the extracts 14 times within 7 weeks in the build-up phase. This schedule was included in the Chinese guideline on AIT in 2017.158 Apart from SCITs targeting HDMs, several cluster schedules targeting grass pollen159, 160 and venom161 have been developed.

Rush schedules

Rush immunotherapy (RIT) is one of the methods for accelerated AIT. Its purpose is to shorten the dose-accelerating stage and reach the dose maintenance stage faster, reducing the number of patient visits and treatment time, improving symptoms sooner, and improving patient compliance. Studies have shown that using standardized antigens for RIT is safe and effective after drug pretreatment.162, 163, 164, 165, 166, 167 Patients in most areas of China are allergic to mites. Since 2012, Chinese researchers have conducted clinical studies on the safety and effectiveness of RIT in treating AR using standardized mite antigens. Furthermore, some studies have been conducted to examine the mechanism of RIT and how to conduct drug preconditioning.168, 169, 170 Presently, nearly 10 hospitals in China have performed clinical trials using RIT (Table 4). However, due to the high risk of RIT, a multi-center study with a large sample size is needed to validate it for general application. Therefore, as RIT is not routinely recommended in China, caution should be taken in its application.

Table 4
Rush immunotherapy schedule

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Dose adjustments

Dosage can be modified to make up for missed injections, and different adjustment rules apply to the build-up (Table 5) and maintenance phases (Table 6).

Table 5
Dose adjustment rules in the build-up phase

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Table 6
Dose adjustment rules in the maintenance phase

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It is suggested that if the diameter of the local urticaria exceeds 5 mm within 24 hours after injection, the dose should not be increased. Initiating AIT should be avoided during seasons of peak allergen exposure. The first dose should not exceed 50% of the last dose because each injection is in a new package. In cases of vaccine change, the immunotherapy procedure should be adjusted. According to Chinese government policy (National Health Commission of the People’s Republic of China), there are no restriction intervals between inactivated vaccines and all oral vaccines; however, there should not be fewer than 28 days between injection doses of live vaccines. Approximately 90%–95% of recipients of a single dose of live vaccine administered by injection developed protective antibodies within 14 days of the dose, indicating that the optimal space between 2 vaccines is more than 14 days.171 During the build-up phase, the patient can receive other vaccines, including the COVID-19 vaccine, 1 week after the allergen injection, followed by the regular allergen vaccine (second allergen injection). Additionally, the dose should be half of the last allergen vaccine dose. During the maintenance phase, the patient can receive other vaccines 1 week after the allergen injection, and 3 weeks later the patient can continue the immunotherapy schedule.

AR patients

In the management of AR patients, SCIT in combination with pharmacotherapy, physical therapy, and allergen avoidance can improve the clinical efficacy and safety of the treatment. Therapy before, during, and after immunotherapy should be administered according to patient-specific requirements.172

Glucocorticoid nasal spray is the first-line treatment for AR. Oral or topical antihistamines can relieve nasal itching, sneezing, and runny nose. Furthermore, the combination of glucocorticoid and antihistamine nasal spray is more effective than a single drug. Avoidance of airborne pollutants, such as cigarette smoke, is also important for controlling AR.173

AR with asthma

Historically, since AR and asthma exhibit common physiological and immune inflammatory mechanisms, they were considered different manifestations of the same allergic airway disease in the upper and lower airways, which means “one airway—one disease.”176, 177 Moreover, AR is one of the risk factors for asthma, and the worldwide prevalence of AR is reported to be over 85% in patients with asthma.178 In China, approximately 70% of asthmatic patients have AR, whereas only 10% of patients with AR have asthma.20, 179

Management of patients with both AR and asthma is similar to that of asthmatic patients. AIT may be an option for these patients to effectively manage multiple symptoms. Moreover, in compliance with the review for personalized asthma care, Global Initiative for Asthma (GINA) 2021, which includes asthma diagnosis and assessment, and treatment and adjustment, is needed.180 Studies have shown that AIT can ameliorate symptoms in patients, reduce medication requirements, and reduce the incidence of asthma and AR.181, 182, 183

Long-term treatments of asthma include controller medications, reliever medications, and add-on therapies for severe patients. For adults and adolescents, an inhaled corticosteroid (ICS)-containing controller treatment, which is a personalized asthma management, should be received as soon as asthma is diagnosed. In mild asthma, treatment with low-dose ICS-formoterol could be an effective alternative to relieve symptoms and reduce the risk of exacerbation. The response and possible side effects of asthmatic patients to treatments should be monitored and routinely reviewed to adjust treatment to any variable conditions. Controller medication can be adjusted in a stepwise manner during the AIT process for effective treatment and symptom management as stated in the GINA.184

Children

The treatment of patients with allergic diseases involves 2 aspects: in-hospital management and out-of-hospital management, which is achieved through patient, family, and caregiver education (including follow-up education).185 In-hospital management involves electronic and hardcopy (paper) medical databases, whereas out-of-hospital management mainly includes patient education, telephone reminders, and patient follow-up.186

Additionally, it is necessary to inform patients of the advantages and disadvantages of the treatment chosen, duration of treatment, possible adverse reactions and the risk of severe allergic reactions, costs, therapy efficacy, and long-term benefits.187 In addition to telephone follow-up, communication via internet could be employed to establish close communications between physicians and patients, which can improve treatment efficiency and facilitate the recovery process.130, 188 China Children’s Asthma Action Plan (CCAAP) is a scientific, practical, and professional electronic management platform for improving the care and management of children with asthma. A similar management approach could be applied to SCIT in children.

Subjective evaluation

Based on the Chinese guidelines for the immunotherapy of AR, it is recommended that AIT be initiated earlier for effective treatment outcomes.158 Once AR is diagnosed and the relevant causal allergen identified, AIT should be considered the initial treatment option.149 Clinical studies have shown that 85.4% of patients were responsive to SCIT therapy after 3 years of SCIT.189

SCIT can relieve nasal mucosal inflammation in AR patients, reducing mucosal pallor and edema, and significantly improve nasal symptoms including congestion, discharge, itching, and sneezing.189, 190 SCIT can significantly reduce the need for allergy medications as well as improve the quality of life and mental health status of AR patients.148, 191 SCIT can attenuate both the upper and lower airway immune responses to nasal allergen exposure in patients with AR and/or asthma.192 Patients with AR and asthma were treated with SCIT for 3 years and followed-up for 2 years; the results indicated that SCIT had a long-term effect in reducing the risk of asthma development.190 An analysis of SCIT in children with AR and cough variant asthma showed that SCIT not only significantly improved the clinical symptoms, but also prevented the development of new sensitization and typical asthma.193 An analysis of SCIT efficacy showed that HDM-SCIT significantly improved nasal symptoms and quality of life in children and adults with AR, with longer effects in children than in adults.189, 194 For AR patients sensitized to multiple aeroallergens, SCIT treatment can also significantly improve clinical symptoms.148

Moreover, several studies have confirmed that SCIT exhibits long-term effects in AR patients.115, 148, 195 A long-term follow-up study of AR patients who received 3 years of SCIT showed that clinical efficacy lasted for at least 5 years.195 Sahin et al.196 showed that the positive effects of SCIT were evident in patients 10 years after HDM-SCIT.

SCIT can be divided into conventional and cluster immunotherapy during the dose accumulation phase. Studies have found that cluster immunotherapy can significantly reduce nasal symptoms in AR patients, with rapid effects compared to conventional immunotherapy. Moreover, compared to the conventional immunotherapy regimen, the cluster regime did not significantly affect the incidence of local or systemic adverse reactions during the dose accumulation and dose maintenance phases.197, 198 Therefore, cluster immunotherapy could be a safe, rapid, effective treatment procedure for AR.

Nasal allergen provocation test

NAPT is required to imitate the natural environment or conditions in order to determine specific allergens. Clinicians use sprays directly or place suspected causative antigens into the nasal cavity to observe which antigens trigger pathophysiological reactions for diagnosis. NAPT has been regarded as a safe and straightforward technique for the diagnosis of AR. NAPT is the internationally recognized “gold standard” for the diagnosis of AR and applied to identify the disease phenotype before commencing AIT in order to ascertain allergens. The results of NAPT include subjective assessments (VAS and total nasal symptom score) and objective assessments (peak nasal inspiratory flow, acoustic rhinometry, and active anterior rhinomanometry).199

Biological markers

Biomarkers play an important role in predicting the efficacy of AIT and monitoring the treatment response. There are 6 classes of potential biomarkers of AIT: antibodies (total IgE, sIgE, sIgE/IgE ratio, sIgG1, sIgG4, sIgE/IgG4 ratio, and sIgA); basophil activation (CD63, CD203c, and basophil histamine release); cytokines and chemokines (IL-4, IL-10, IL-13, IL-9, IL-17, and eotaxin); cellular markers (Tregs, Bregs, and DCs); serum inhibitory activity for IgE (IgE-FAB); and allergen provocation tests (SPTs, intradermal test, nasal provocation test, and environmental exposure chamber).200

Serum sIgE level is an inclusion criterion for the initiation of immunotherapy. Moreover, because of their high specificity and easy detectability, antibodies, especially sIgE, sIgG4, and the sIgE/IgG4 ratio, have been widely used to predict the efficacy of clinical immunotherapy and evaluate response. However, antibody levels are not always consistent with clinical outcomes.

Data regarding the clinical relevance of HDM components over AIT for AR are lacking. Huang et al.201 examined the serum sIgE and sIgG4 level of 18 adult AR patients receiving HDM AIT for 52 weeks and found that Der p1, p2, p23, Der f1, and f2 were important sensitizing components of HDM. Der p1 appears to be the most clinically relevant allergenic component for effective AIT.

Basophil activation is measured by flow cytometry using the dose-response curves after allergen stimulation in vivo. Surface markers used in basophil activation tests include CD63, CD203c, and diamine oxidase. Most studies use CD63 as an activation marker, whereas CD203c is basophil-specific. The basophil activation test has been used to monitor the effects of AIT and other immune modulatory therapies.202 Decrease in basophil activation after SCIT was reported in patients with allergic rhinoconjunctivitis caused by grass pollen.203

Weihong et al. 204 evaluated serum cytokines in 72 pediatric AR patients receiving SCIT. Multiple cytokine profiling was conducted via Luminex assay at baseline, and 48 selected cytokines were tested and compared between the defined effective (n = 46) and ineffective group (n = 23). The serum eotaxin, interferon (IFN)-γ, IL-4, and MIF levels were closely associated with the efficacy of SCIT in HDM-induced pediatric AR patients. Further, enzyme-linked immunosorbent assay validation results in a cohort of 80 pediatric patients demonstrated that serum eotaxin and IL-4 levels were increased in responders, whereas IFN-γ levels decreased significantly (P < 0.05 for all); ROC curves revealed that serum IL-4 exhibited more reliable accuracy in predicting SCIT efficacy than eotaxin and IFN-γ.

IgE-FAB measures the serum inhibitory activity for IgE after AIT by flow cytometry. Some data support the role of IgE-FAB in predicting the efficacy of AIT. The IgE-FAB assay technique is complex and can only be performed in specialized laboratories, limiting its clinical application.205

Apart from in vitro examination, in vivo biomarkers, including various allergen provocation tests, have been used to evaluate the curative efficacy of AIT. In addition to the biomarkers mentioned above, Ma et al.206 recently reported that serum leukotriene A4 hydrolase (LTA4H) increased significantly after 1-year SCIT, which could be used as a new biomarker for AIT.

Efficacy in adults

Efficacy in children

In China, SCIT has been widely used for the treatment of allergic diseases in children since the 1990s. Over the past 20 years, several national academies and guidelines have recommended the integration of SCIT into the standard treatment for AR.129, 185, 216

According to current guidelines based on the latest evidence, allergen-specific immunotherapy should be administered to children with moderate to severe AR, and the recommended starting age is 5 years old.217, 218 Several studies have confirmed the reliable therapeutic effect of AIT in children with AR.148, 219 For instance, a study reported a considerable decrease in symptom scores after 4 months of allergen-specific immunotherapy, and these continued to decline during a period of 12-month SCIT.220 Wang et al.217 found that the level of serum sIgG4 increased significantly after 1-year SCIT treatment. These results are consistent with the previous findings of Zhang et al.155, 220 who observed considerable improvements in symptoms within the first year of specific subcutaneous injection treatment; however, patients were prone to recurrence of symptoms. Wang et al.217, 221 reported that improvement in symptoms remained stable in the second and third years of SCIT. Several clinical investigations revealed that 2–3 years of SCIT is more effective than traditional medical treatment for treating clinical symptoms and improving the quality of life of children with AR, and that the clinical benefits persist for more than 5–10 years after treatment cessation.222, 223 SCIT has an ideal long-term protective effect in children with AR; however, it takes at least 2–3 years of treatment for a sustained therapeutic effect. Song et al.148 found that single-allergen SCIT is beneficial for treating AR caused by multiple allergens in pediatric populations. Furthermore, Penagos et al.222 showed that SCIT had better effects in children with AR than in adults with AR. The optimal time for SCIT is during childhood because the immune systems of children are not fully matured.

AIT is the only etiological treatment for AR, it involves regulating the natural process of AR through immune regulation mechanisms.224 HDM is the most common allergen responsible for AR in China.224 Because of the existence of cross antigen mechanisms, the number of allergens, including HDMs, is 2–3, which is also the indication of single HDM SCIT. SCIT can significantly improve the symptoms and quality of life of children with AR during a long period of time, and it is significantly better than conservative treatment. SCIT does not only have an early curative effect, but also a long-term curative effect. Studies have shown that 3-year SCIT can significantly improve HDM respiratory allergic reactions and 5-year SCIT can improve clinical symptoms of AR.181 Moreover, there was a decrease in the incidence of new allergic reactions during treatment and several years after the completion of SCIT,225 with a significantly reduced risk of asthma.133 Furthermore, some research reports suggest that the impact of SCIT in children is better than that in adults.189

Adverse reactions

SRs

SCIT is a safe well-tolerated treatment if injections are given in a medical setting by experienced physicians.

Previous studies suggest that the incidence rate of SRs in AR patients range from 1.3% to 14%.132, 232, 233, 234, 235 The incidence rate of SRs per injection with conventional nonaccelerated build-up protocols is about 0.1%–0.2%,233, 236 although it is higher if accelerated cluster or rush build-up regimens are used.237, 238 The incidence of fatal severe reactions was reported as 1 event per 1–2.5 million injections233, 238, 239 in the past, whereas new data collected in the North American Surveillance Study between 2008 and 2019 showed a decrease in incidence to 1 in every 7.2 million injections.240 As expected, most SRs (75.8%) occurred during the up-dosing phase.139

SRs to SCIT can range from mild to severe adverse reactions in the skin, gastrointestinal tract, upper and lower airways, or the cardiovascular system. Several classifications of SRs during AIT have been proposed, including the EAACI 2006 Grading System241 (EAACI2006), WAO 2010 Grading System236 (WAO2010), WAO 2017 Grading System232 (WAO2017), and AAAAI/ACAAI Grading System.242 The detailed grading systems are shown in Table 7.243

Table 7
The different international grading systems (EAACI2006, WAO2010, and AAAAI/ACCAI)

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Although different grading systems and severities are closely related, there are variations in the grading of mild and moderate SRs. Both the AAAAI/ACAAI classification and the EAACI2006 classification are easily administered and reliable. The main limitations in the EAACI2006 classification are the lack of gastrointestinal symptoms, the rigid definition of “early onset” as 15 minutes, and the lack of precision of some terms. The WAO2010 classification was based on the organ system(s) involved and reaction severity. The final grade is determined by the physician/health care professional after the event is over. The WAO2010 classification system is considered more practical and convenient for diagnosis and helpful in accurately deciding when epinephrine should be used. The WAO2017 classification has not been endorsed by the WAO, and the correlation between the grade and SR severity is lower in this classification system compared with the WAO2010. Although these classification systems have been used in several clinical reports and reviews, they are yet to be clinically validated.243

Delayed reactions are defined as SRs occurring more than 30 minutes after injections. Skin disorders, particularly urticaria, were more frequently observed after 60 minutes. Incidences of delayed reactions have been estimated to be 14%–15% of all SRs,233 with only 0.5% of SRs occurring after 60 minutes. Most of these delayed SRs were rated as mild or moderate, were rarely fatal. For patients with delayed SR, it would be advisable to increase their wait time to 45–60 minutes or longer. Because of poor adherence with epinephrine self-administration, prescribing autoinjectors for all patients is highly controversial. Thus, it is not an effective alternative to observing patients for at least 30 minutes following SCIT injections.233

Before discharge, patients should be counseled on the possibility of biphasic reactions. Biphasic reactions from occur in 10%–23% of patients, at a median time of 5.5 hours, and are typically milder.244, 245

Risk factors

AIT is contraindicated in patients with medical conditions that might increase the risk of treatment-related severe SRs, such as those with severe or poorly controlled asthma or with significant cardiovascular disease (e.g., unstable angina, recent myocardial infarction, significant arrhythmia, and uncontrolled hypertension). Therefore, AIT should be administered with caution to patients receiving β-blockers or angiotensin-converting enzyme inhibitors. Risk factors for SCIT-related SRs include symptomatic asthma, prior SCIT-related SRs, and higher degree of skin test reactivity.139 Other potential risk factors for SCIT-related SRs, such as administration during the height of the pollen season, build-up dosing schedule (cluster vs. conventional), and treatment phase (maintenance vs. build-up phase) have been suggested, but none have been clearly established.238 Dong et al.246 reported that SRs during immunotherapy are high in young asthmatic patients with high degree of allergen sensitivity. Some risk factors for severe AEs and fatal events are shown in Table 8.244, 247, 248, 249, 250

Table 8
Conditions potentially associated with subcutaneous immunotherapy-related systemic reactions

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Safety in children

Among Chinese children, SCIT-related adverse reactions occurred at a rate of 38.4% per patient and 10.0% per injection during SCIT for AR and bronchial asthma.251 LRs accounted for 88.9% of the adverse reactions, and occurred at a rate of 35.6% per patient and 8.9% per injection during SCIT, with intense LRs observed in only 2.8% of patients (wheal diameter > 8 cm).251 Additionally, the majority (80.2%) of LRs occurred within 60 minutes of injection.231 SRs accounted for a minority (11.1%) of the adverse reactions,251 and occurred at a rate of 0.5%–2.60% per injection and 9.2%–19.3% per patient during SCIT.227, 231, 246, 251, 252, 253 Some patients experienced SRs 2 times or more.231, 253 According to the World Allergy Organization SCIT SR grading system, all the SRs reported ranged from grades 1 to 3, and no grades 4 or 5 SRs were reported.227, 231, 252, 253 Additionally, no fatal cases were reported.148, 251 Most SRs occurred during injection of No.4 vial (AlutardDp vaccine),231, 253 and approximately 89.3%–95.8% occurred within 30 minutes of injection.227, 246, 253 Treatment with medications, such as β₂ agonists and H1 antihistamines, was generally effective against SRs; however, intramuscular injection of epinephrine was occasionally necessary.231, 246, 251, 253 The prevalence of SRs was higher in children 5–11 years old than in children 12–17 years old.253 SCIT has a safe profile in children with allergic diseases.254

Safety comparison of different schedules

Studies have shown that there was no significant difference in the incidence of systemic AEs between cluster and conventional SCIT. During the maintenance phase, similar improvements in quality of life and reduced skin reactivity were observed in both groups, but no significant changes in sIgE were observed.155 There was no significant difference in the incidence of LRs or SRs during the build-up and maintenance phases between the cluster and conventional schedules.197, 255, 256 Conventional and cluster SCIT are important immune-modifying treatment schedules for both children and adult AR patients, with similar efficacies in both adults and children.257 The cluster schedule is as safe as the conventional schedule for AR patients with or without asthma.156

Conventional immunotherapy is effective in treating AR; however, the treatment strategy is limited by poor patient compliance, delayed efficacy, and patient frustration. RIT is a technique for treating allergic patients using a series of injections of allergenic extracts until an immunizing (maintenance) dose is attained within a short period of time.258, 259, 260 RIT offers the advantages of rapid response, improved compliance, and cost-effectiveness, and can shorten treatment duration from 4 months in conventional schedules to less than 1 week.254 However, considering the high risk of serious adverse reactions compared to the conventional immunotherapy,261, 262, 263 its use is limited in China. There are few studies on RIT for AR.254 Most published RIT studies have focused on allergic patients with venom. Most venom RIT studies have demonstrated that the efficacy and safety of venom RIT are equivalent to or better than those of conventional schedules.261

Studies on RIT in AR patients with or without asthma suggest that RIT without premedication can increase the risk of SRs, with SR rates of 27%–100% for patients without premedication and 7.2%–27% for patients with premedication. Premedication appears to reduce the SR rate to a range that is comparable to conventional build-up schedules, which is 0.84%–28.6%.261 Qiu et al.169 compared the safety and efficacy of RIT and conventional immunotherapy in Chinese AR patients. For safety, all RIT patients were hospitalized for 6 days and received oral antihistamines and corticosteroids during RIT. Results showed that the LR rates of the RIT and conventional immunotherapy groups during the build-up phase were 32.45% and 30.86%, respectively. In contrast, SRs were observed in 12.2% and 12.5% of all patients in the RIT and conventional immunotherapy groups, respectively. Therefore, it can be concluded that the safety and efficacy of RIT in premedicate AR patients is similar to those in patients undergoing conventional immunotherapy.

Although there have been several reports on the safety of RIT and a decrease in the incidence of allergic reactions, especially systemic allergic reactions after premedication, there is a lack of large-scale research reports on patients in China. Therefore, allergists should be careful in patient selection for this procedure because anaphylaxis can occur. Due to careful patient selection, routine premedication, and lower targeted end-point dosage, the risk of SRs has reduced considerably264; however, RIT should be performed in medical institutions under the supervision of experienced professionals to ensure safe and effective immunotherapy for AR.254, 261, 264, 265

Prevention

Factors that contribute to adverse reactions during AIT include patient-related factors (sex, age, asthma, and high sensitivity constitution), antigenic vaccine factors (antigenic component and administration route), and dose-related factors of antigen vaccines (administration mode, history of allergic attack), etc.

Based on the above risk factors, the following considerations should be noted to prevent serious adverse reactions caused by AIT:

Treatment of adverse reactions

Generally, most patients are tolerant to AIT, but a few adverse reactions require appropriate treatment. The rules and procedures for managing local and systemic adverse reactions are outlined below.

Mild LRs, such as redness, irritation, or swelling at the site of injection, can usually be relieved using topical corticosteroids, ice packs, or oral antihistamines.267 However, patients with mild adverse reactions should be observed closely and any worsening symptoms should be evaluated carefully as potential signs of anaphylaxis.

Due to the risk of anaphylaxis, more attention should be paid to LRs and SRs, especially for SCIT.268, 269 Early signs should be identified including itching of the palms and soles, perianal or peri-genital pruritus, bellyache, urge to defecate and urinate, sneezing attacks, and generalized pruritus. Subsequently, respiratory and/or cardiovascular symptoms may appear.265 The management of severe local and systemic adverse reactions in SCIT is summarized in Table 9.241, 270, 271, 272

Table 9
Management of adverse reactions in subcutaneous immunotherapy

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Since adverse reactions usually occur within 30 minutes after injection, patients must be observed for at least 30 minutes following injection. Additionally, injections must be administered by experienced clinicians in a standard hospital well equipped with emergency facilities including the following apparatuses: trolleys for patient to lie flat if needed; electrocardiographs, pulse oximeters and blood pressure monitors; oxygen and suction devices, including tubing and masks; airway management devices for intubation and cricothyrotomy; intravenous infusion pumps; nebulizer masks (for inhaled epinephrine); manual blood pressure cuffs; intravenous access cannulae (20–16 G) and giving sets; and needles and syringes.272

As recommended in the guidelines, it is essential to carefully examine patients and their medical histories before administration of each injection. PEF evaluation must be performed before each injection, especially for AR patients with asthma. PEF values of less than 70% of the best predicted is considered a warning signal.272 Most of the severe systemic AEs can be prevented if physicians abide by these rules.

In comparison to SCIT, SLIT has a less worrisome safety profile, as SRs are rare. Although no SLIT-associated severe systemic adverse reactions have been reported in China, patients should be educated on the possible adverse reactions they might experience during the procedure.