Subcutaneous Allergen Immunotherapy for Allergic Disease

Examining Efficacy, Safety and Cost-Effectiveness of Current and Novel Formulations

Linda Cox; Moisés Calderón; Oliver Pfaar


Immunotherapy. 2012;4(6):601-616. 

In This Article

Systematic Reviews & Meta-analyses

Systematic reviews and meta-analyses have been conducted to evaluate the efficacy and safety of SCIT for AR and asthma.[13] Well-conducted systematic reviews and meta-analyses are still considered powerful instruments for synthesizing clinical trial data, providing a straightforward answer to a specific pre-established question: is there is a beneficial effect between the therapeutic intervention (such as SCIT) and the placebo?[14]

In this statistical analysis, researchers have conducted systematic reviews of SCIT, which have included studies with small numbers of patients. One potential problem with small studies is that they may not be sufficiently powered to establish a positive effect when one is present, which is referred to as a type II error. A meta-analysis can combine the results of individual studies and increase the power of the analysis providing the interventions and outcomes in the various studies are sufficiently similar. However, because of the significant clinical and methodological heterogeneity of SCIT studies, it may be difficult to directly compare studies unless the results of each study are standardized by calculating the standardized mean difference (SMD). The SMD is the difference of the means of both treatment arms divided by the pooled standard deviation. In this way, the treatment effect in each study is expressed in standard units (instead of the original units). "Efficacy can be expressed as 'numbers needed to treat' (NNT), which is the number of people who need to be treated to benefit one additional person over placebo and can be calculated by the following formula:

The ideal NNT is 1, where everyone improves with treatment and there is no improvement in any of the control group. Generally, the higher the NNT, the less effective is the treatment".[15]

The heterogeneity of studies is reflected in the I2, which provides an estimate of the variability across studies that is likely due to a true difference in treatment effect and not chance. A higher I2 (>0.5) correlates with greater heterogeneity.

Allergic Rhinitis

Three meta-analyses have been published evaluating the efficacy of SCIT for AR. Klimek et al. published in 1999 the first so-called "meta-analyses of SCIT on clinical and immunologic treatment used in patients with allergic rhinoconjunctivitis".[16] They included 43 RCTs published between 1980 and 1997. In this thorough literature review, the authors found that SCIT was effective in the treatment of allergic rhinoconjunctivitis, decreasing symptoms, the need for medication, and reactivity in specific nasal and conjunctival provocation tests, as well as inflammatory markers. The authors concluded that the efficacy of SCIT is dependent on certain characteristics of the allergen to which the patient is sensitized, these being:

  • The allergen itself

  • Its quality

  • The amount used during SCIT

  • The schedule used

In 2000, Ross et al. published a second analysis of SCIT for treating AR.[17] Sixteen prospective, single-blind or double-blind, placebo-controlled studies published between 1966 and 1996 were included. The experimental designs varied considerably from one study to another; therefore, it was not possible to reduce the entire database to a single format for statistical analysis. However, odds ratios (ORs) and 95% CIs were calculated using a random-effects model for a variety of clinical outcomes. All but one study concluded that SCIT was effective in terms of reducing the symptoms of AR compared with placebo (OR: 1.81; 95% CI: 1.48–2.23).

In 2007, Calderón and colleagues published the first Cochrane systematic review and meta-analysis evaluating the effect of allergen injection immunotherapy on seasonal AR.[18] The following are the characteristics of the studies included in this systematic review:

  • Fifty-one RCTs published between 1984 and 2006 were included;

  • A total of 2871 patients (1645 active and 1226 placebo);

  • Each patient received on average 18 injections;

  • The seasonal allergens used in these included studies were ragweed (12 trials), mixed grass (16 trials), timothy (five trials), Parietaria (six trials), birch (four trials), orchard (two trials), cedar (three trials), bermuda (one trial), Juniperus ashei (one trial) and Cocos nucifera (one trial);

  • Twenty-seven studies included patients with mild-to-moderate seasonal allergic asthma, six studies had no coexistent asthma and in 18 studies the status of asthma was not specified;

  • The types of vaccines used were extracts (38 studies), allergoids (12 studies) and nonspecified (one study);

  • The duration of maintenance treatment and the period of follow-up varied considerably between studies, largely reflecting preseasonal, coseasonal and postseasonal administration;

  • The duration of immunotherapy varied from 3 days (minimum duration) to 3 years (maximum duration). Six studies did not mention the duration of treatment;

  • It was not possible from most of the studies to determine accurately the dose of allergen given in terms of micrograms of major allergen. Doses given were quantified in many different proprietary units including BU, PNU, SQ-U, mg Ag, SE-U, AUeq, SU/ml, TU, wt/vol and HEP.

Meta-analyses were performed for the symptom and medication scores (Table 1):

  • Symptom score (data from 15 trials): there was an overall reduction in the immunotherapy group with a SMD of -0.73 (95% CI: -0.97 to -0.50); I2 = 63% (moderate heterogeneity);

  • Medication score (data from 13 trials): there was an overall reduction in the immunotherapy group with a SMD of -0.57 (95% CI: -0.82 to -0.33); I2 = 64% (moderate heterogeneity).


The clinical efficacy of SCIT in allergic asthma has been evaluated by Abramson and colleagues in three systematic reviews and meta-analyses, all of them are the consecutive updates.

The first review was a systematic review and meta-analysis of 20 trials in asthma published between 1954 and 1990.[19] Subsequently, this systematic review was updated as a Cochrane meta-analysis to include 75 trials published between 1954 and 2001.[20] The following are the characteristics of the studies included in the last systematic review:[21]

  • Eighty-one RCTs published between 1950 and 2005 were included;

  • A total of 3792 patients (3459 with asthma) were involved;

  • The allergens used were house mite (42 trials; Dermatophagoides pteronyssinus or Dermatophagoides farinae), pollen (27 trials; bermuda grass, orchard grass/cocksfoot, timothy grass, velvet grass, sweet vernal grass, perennial rye grass, birch, olive or ragweed pollen), animal dander (ten trials; cat and dog), Cladosporium mold (two trials), latex (two trials) and multiple allergens (six trials);

  • The types of vaccines used were natural extracts and allergoids.

The results of these meta-analyses on the effect of SCIT on asthma showed that ( Table 2 , Table 3 , Table 4 and Table 5 ):

  • There was a significant reduction in asthma symptoms and medication and improvement in bronchial hyper-reactivity following immunotherapy;

  • There was a significant improvement in asthma symptom scores (SMD: -0.59; 95% CI: -0.83 to -0.35);

  • It would have been necessary to treat three (95% CI: 3–5) patients with immunotherapy to avoid one deterioration in asthma symptoms;

  • It would have been necessary to treat four (95% CI: 3–6) patients with immunotherapy to avoid one requiring increased medication;

  • Allergen immunotherapy significantly reduced allergen-specific bronchial hyper-reactivity, with some reduction in nonspecific bronchial hyper-reactivity as well;

  • There was, however, no consistent effect on lung function. The investigators stated that the benefits of allergen immunotherapy could be overestimated because of unpublished negative studies, and suggested that additional studies would be necessary to overturn these results.

It was concluded that allergen immunotherapy is a treatment option in highly selected patients with extrinsic ('allergic') asthma.

Ross et al. also evaluated the effect of SCIT in asthmatics from 24 prospective trials published between 1966 and 1998.[22] A random-effects model was used. The SCIT group showed an improvement compared with the placebo group for symptoms of asthma (OR: 2.76; 95% CI: 2.22–3.42), pulmonary function (OR: 2.87; 95% CI: 1.82–4.52), protection against bronchial challenge (OR: 1.81; 95% CI: 1.32–2.49) and reduced need for medications (OR: 2.00; 95% CI: 1.46–2.72).

Venom Immunotherapy

Systemic reactions (SRs) to Hymenoptera stings, both flying and imported fire ants, especially when associated with respiratory symptoms, cardiovascular symptoms, or both, and positive skin test or in vitro test results for specific IgE, are an indication for allergen immunotherapy.[23] In the USA, patients aged older than 16 years with a SR limited to the skin are also candidates for allergen immunotherapy. Patients 16 years or younger who present with only a cutaneous reaction to Hymenoptera stings might not require immunotherapy.

Ross et al. conducted a meta-analysis, published in 2000, in which they compared the effects of SCIT in the treatment of Hymenoptera venom hypersensitivity.[24] Eight studies published between 1966 and 1996 were included (total of 453 patients). The authors found that the symptoms of Hymenoptera venom hypersensitivity were prevented in 79% of the 101 patients receiving SCIT versus 36% of the 136 comparison patients (OR: 2.20; 95% CI: 1.72–2.81).


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