Subcutaneous immunotherapy

Efficacy and safety

Inhalation allergens

The clinical manifestations of atopic sensitivity to inhalant allergens include rhinitis, conjunctivitis, and asthma. From a clinical point of view, the only parameters that indicate efficacy of a treatment are reductions in symptoms and/or drug intake of a magnitude that significantly reduces morbidity (1). The clinical efficacy of subcutaneous immunotherapy is confirmed by 75 double-blind, placebo-controlled studies published from 1980 to 2005 which demonstrate clinically relevant decreases in symptom-medication scores. Fifteen out of the 75 studies included children.

The category of evidence for clinical efficacy is ‘Ia’ for asthma and ‘Ib’ for rhinitis using allergen products from birch, grasses, mountain cedar, cypress, olive, Parietaria, ragweed, cat, D. pteronyssinus, Alternaria, Cladosporium.

Fundamental questions are whether immunotherapy has the potential to provide long-term benefit following its discontinuation and whether immunotherapy may prevent either disease progression and/or the onset of new allergic sensitivities (2). Without long-term reduction in disease severity and disease modifying capability, immunotherapy may not be cost-effective, and consequently not be a real alternative to pharmacologic treatment (3). Some older studies indicate that the treatment may have a long-lasting effect. The study of Durham et al. (4) is the only available controlled study which documents long-term efficacy of immunotherapy following a double-blind, placebo-controlled withdrawal of the treatment (5).

The category of evidence for long-term efficacy and preventive capacity is ‘Ib’.

A major limitation for the wider dissemination of allergen-specific immunotherapy is the associated risk of systemic side-effects. The injection of allergens into an IgE-sensitized individual always implies a risk, however small, of inducing anaphylactic side-effects (1, 3, 6). The frequency and severity of systemic reactions vary between studies, depending on the criteria for patient selection, the disease, the allergen product and formulation used, and the type of induction regimen. Evidence suggests that the patients most likely to develop anaphylaxis are those who are highly allergic based on skin tests or specific IgE-tests and patients with more severe disease, particular those with chronic and uncontrolled asthma (7). Systemic side-effects occur more frequently in patients during the induction (up-dosing) phase of treatment when compared to maintenance therapy (8, 9).

Hymenoptera venom allergens

Detailed information is available in the position paper on venom allergy of the EAACI task force for insect venom allergy (10).

The efficacy of venom immunotherapy has been analysed in three controlled (11–13) and several prospective uncontrolled studies which employed a usual maintenance dose of 100 μg of venom. In these studies, patients were monitored with sting provocation tests during immunotherapy (14). In all controlled trials analysing patients with either vespid, honey bee or ant venom allergy, comparing venom with either whole-body extract or placebo, a highly significant difference in favour of venom was observed: 75–100% of venom-treated patients tolerated re-sting without allergic symptoms, while 64–75% of whole-body product and 58–72% of placebo-treated patients developed systemic allergic reactions on re-sting challenge. In the prospective uncontrolled studies (14) only 0–9% of vespid allergic but around 20% of bee venom allergic patients still reacted to the challenge with the respective insect. These studies confirm the superior efficacy for immunotherapy with vespid or ant venom when compared with honey bee venom. In patients who did react following a course of venom immunotherapy, the symptoms were usually mild and less severe than those observed before treatment.

The category of evidence for efficacy is ‘Ib’.

The safety of venom immunotherapy is related to the nature of the venom used and the protocol. Definitely more side effects are observed during honey bee venom than vespid venom treatment (15). In an EAACI multi-centre study (16) in 840 patients totalling 26 601 injections, 20% of patients developed mostly mild systemic allergic reactions, corresponding to 1.9% of injections during the dose increase phase and 0.5% during the maintenance phase. Rapid dose increase, especially with high cumulative daily doses of 200–500 μg in rush protocols seemed to increase the risk of side effects.

Indications and contraindications


Immunotherapy is indicated for confirmed IgE-mediated disease using standardized products with documented clinical efficacy and safety (grass, birch, ragweed, olive, Parietaria, cypress, cat, house dust mites (D. pteronyssinus, D. farinae) (6). Immunotherapy is indicated as a supplement to allergen avoidance and to pharmacotherapy. Normally subcutaneous immunotherapy is restricted to patients above 5 years of age. Below this age inhalation allergens play a less important role. Furthermore, when subcutaneous allergen-specific immunotherapy is prescribed below 5 years of age, it is critical that the physician responsible for the injections has experience in identifying and treating emerging signs of anaphylaxis in this age group. In addition nurses and other staff administrating allergen injections to children must be especially trained to treat this age group. Except for insect venom allergy subcutaneous immunotherapy is rarely used after the age of 60 years.

Immunotherapy is not indicated for the treatment of food allergy and atopic eczema.

Indications in rhinoconjunctivitis and asthma. 

  • • Patients with symptoms induced predominantly by allergen exposure.
  • Patients with clinical symptoms due to a single or few allergens.
  • Patients with a prolonged season or with symptoms induced by succeeding pollen seasons.
  • Patients with rhinitis and symptoms from the lower airways during peak allergen exposure.
  • Patients in whom antihistamines and moderate dose topical glucocorticoids insufficiently control symptoms.
  • Patients who do not want to be on constant or long-term pharmacotherapy.
  • Patients in whom pharmacotherapy induces undesirable side effects.

It is recommended that the indication follow the guidelines of the EAACI Immunotherapy Position Paper (3). The indication for allergen-specific immunotherapy should be explicitly defined in relation to:

  • Disease and disease severity.
  • Allergens and the importance of allergen sensitization.
  • The need for and the effect of symptomatic treatment.
  • The risk of the disease and the treatment.
  • Psychological factors.
  • The patient's attitude to the disease and treatment.

Indication in Hymenoptera venom allergy.  Venom immunotherapy is indicated in both children and adults with a history of severe systemic allergic reactions including respiratory and/or cardiovascular symptoms and documented sensitization to the respective insect as determined by either skin tests and/or specific serum IgE tests (10, 17). As for systemic nonlife-threatening reactions (urticaria, erythema, pruritus) other factors may influence the decision to initiate venom immunotherapy. These include availability of immediate access to medical care, occupations and/or hobbies where the risk of exposure is high, concomitant cardiovascular disease, the presence of other pathologies such as mastocytosis and psychological factors arising from anxiety which can seriously impair patient quality of life. Immunotherapy is not recommended for large local reactions or unusual reactions, like non-IgE mediated hypersensitivity reactions such as vasculitis, nephrosis or thrombocytopenia (17).

More detailed information are available from the position paper on venom allergy of the EAACI task force for insect venom allergy (10).


The contraindications for subcutaneous allergen-specific immunotherapy with inhalant and Hymenoptera venom allergens include (6):

  • Absolute contraindications.
  •  Serious immunological diseases, major cardiovascular disease (except in case of serious insect venom allergies), cancer, chronic infections.
  •  Severe asthma with persistently reduced lung functions (FEV1) below 70% of predicted in spite of optimal pharmacologic treatment.
  •  Treatment with β-blockers (including topical) (see Hymenoptera below).
  •  Lack of compliance and severe psychological disorders.
  • Relative contraindications.
  •  Pregnancy (no documentation of teratogenic risk), but a risk of anaphylactic reactions during induction phase and consequent damage of the foetus. It is recommended not to start induction during or in case of planned pregnancy. Uncomplicated maintenance treatment may be continued after careful information and acceptance by the patient. The treatment should be terminated by the slightest patient insecurity or the development of complications of immunotherapy
  •  Severe atopic eczema
  • In contrast to inhalation allergen immunotherapy, immunotherapy for venom allergy is often indicated in elderly patients with coexisting cardiovascular disease, who are at a special risk to develop very severe or even fatal reactions. Such patients are not uncommonly on β-blocker treatment. In this situation the risk of stopping the drug must be carefully balanced against the risk of renouncing venom immunotherapy. In coronary heart disease or severe ventricular arrhythmia the risk of stopping the β-blocker can be unacceptable. If highly exposed to the relevant insect, venom immunotherapy may be carried out in patients with ongoing β-blockade but under careful supervision, including monitoring of blood pressure and electrocardiogram and with expertise and remedies at hand if severe side effects with resistance to treatment due to the β-blockade should occur (18).

Preventive and disease modifying capacity

The capacity of subcutaneous immunotherapy to suppress the development of new sensitizations has been investigated in three nonrandomized studies in monosensitized patients (19–21). In an open retrospective study Purello-D'Ambrosio (20) made a follow-up of 7182 monosensitized (to different allergens) patients treated with subcutaneous immunotherapy for 4 years and off immunotherapy for 3 years. The control group consisted of 1214 matched patients followed for 7 years. The development of sensitization to new allergens showed a clinically relevant and statistically significant difference at the 4-year follow-up with figures of 68% in the control group vs 24% in the immunotherapy group and at the 7-year follow-up 78% and 27% respectively. Pajno et al. (21) followed 75 subcutaneous immunotherapy-treated children only sensitized to house dust mites and 63 comparable controls treated pharmacologically for 6 years. In the immunotherapy-treated group 74% continued to be monosensitized vs 33% in the control group. Although these studies are of interest, prospective randomized, controlled studies are needed.

Subcutaneous immunotherapy might prevent the progression of rhinitis into asthma. A multi-centre paediatric study investigated the capacity of immunotherapy in children with allergic rhinitis to down-regulate the development of asthma (22). Children allergic to birch and grass pollen and no symptoms of lower airway hyperreactivity, were randomized to receive either immunotherapy or an optimal pharmacologic treatment. After three years of treatment, the number of children developing clinical asthma was statistically reduced in the immunotherapy group. The development of asthma was 24% in immunotherapy-treated children vs 44% in the drug-treated group, indicating that the high risk of developing symptoms from the lower airways in allergic rhinitic children may be diminished by immunotherapy. Bronchial hyper-responsiveness to methacholine decreased significantly in immunotherapy-treated children, but only two out of 40 children with asthma at inclusion were free of asthma after 3 years indicating that immunotherapy has a greater capacity for preventing than for curing asthma. Further studies are needed to clearly define the preventive capacity of subcutaneous immunotherapy.

Practical aspects


Management plan.  It is rational to organize patient management plans based on a quality-assurance programme, e.g. a systematic description of elements and processes related to the diagnosis and treatment of patients offered allergen-specific immunotherapy.

The aim is to describe current ‘Best Clinical Practice’ in daily clinical work, to define and ensure the chosen level of quality, and to ensure that resources are used in an optimal and rational way.

Competencies.  The physician responsible for management plans involving allergen-specific immunotherapy should optimally be a specialist in allergology (or have equivalent competencies). Special knowledge, education and know-how are demanded for those who treat children.

The indication for allergen-specific immunotherapy should be made by an experienced physician, preferably a paediatrician for children, trained in the evaluation of allergic patients and familiar with the practice of allergen-specific immunotherapy, preferably an allergist.

To ensure safety and efficacy, all staff members involved in allergen-specific immunotherapy should be familiar with common patient scenarios (‘high professional standard’). A high degree of professional knowledge encourages cooperation and ensures the most ‘effective use of resources’.

Staff.  Physicians, nurses and health care persons must be trained and regularly updated in subcutaneous allergen-specific immunotherapy including the observation and rescue treatment of systemic anaphylactic reactions (‘minimal patient risk’).

As a minimum requirement, a competent physician must always be present when subcutaneous immunotherapy is carried out and be responsible for the treatment. In addition, one more person should be available for proper management of serious adverse events.

Responsibility and delegation.  The head of the clinic has the overall responsibility for the performance of subcutaneous immunotherapy and the implementation of safety procedures.

When delegating responsibility the head of the clinic must ensure that the staff member in question is educated to deal adequately with the responsibility, and that the staff member accepts to take on the responsibility.

All staff participating actively in subcutaneous immunotherapy should have clearly defined responsibilities, taken into considerations local principles and practice.

Education of staff members.  The clinic should offer a systematic theoretical and practical education of staff members before their active involvement in subcutaneous immunotherapy.

The head of the clinic is responsible for the maintenance of the knowledge of the staff by continuous internal and external education including the recognition and treatment of anaphylaxis.

When new staff-members are introduced to the programme, it is sensible to assign them a mentor who will ensure their education and help them to master the practical aspects of immunotherapy including:

  • Evaluation of the patients’ condition (in the case that the patient is a child under 15 years of age, parents must be involved in this process) with respect to receiving subcutaneous immunotherapy (clinical state and peak flow measurements).
  • Entering data in the individual patient's ‘Patient Immunotherapy Record Form’ at each visit.
  • Injection technique.
  • Dose modification.
  • Active observation of patients (also children even if they are accompanied by their parents).
  • Early recognition of anaphylactic reactions.
  • Treatment and monitoring of patients with anaphylactic reactions.
  • How to perform scheduled tests and annual assessments.
  • Factors determining decision to continue or conclude therapy.

Rescue equipment.  Essential equipment for the treatment and monitoring of systemic anaphylactic reactions must be available, including (6):

  • Adrenaline (1 mg/ml) for injection.
  • Antihistamine, corticosteroids, and a vasopressor for injection or oral treatment.
  • Syringes, needles, tourniquet, and equipment for infusion.
  • Saline for infusion.
  • Oxygen and suction equipment.
  • Silicone mask and equipment for manual ventilation.
  • Equipment for measurement of blood pressure.
  • Forms for recording the course and treatment of anaphylaxis.

In settings remote from intensive care facilities, equipment for direct laryngoscopy, DC cardioversion, tracheotomy and intracardiac injections may be optional, but the rare situation in which these procedures might be essential does not justify that these procedures are immediately available for subcutaneous immunotherapy.

The responsibility for checking the presence and function of equipment should be delegated to a specified person, and verification should be documented in a logbook.

Communication.  It is rational that all staff members have a mutual responsibility for the treatment and for defined procedures, and feel comfortable with their function. Regular attendance at conferences and educational meetings enhances staff competence.

Deviation from standard operating procedures should be discussed with all staff members involved in relation to correction or definition of new routines.


Due to the commitment needed from both staff members and patients starting subcutaneous immunotherapy, it is important to individualize and adjust the treatment to the patient's age and social background implying that the patient beside the need for treatment also has a need for communication, continuity and coordination of the course of the treatment. Communication with children in agreement with their age and developmental status is a basic demand.

Cooperation with referring physicians.  With respect to patients referred from general practice, the general practitioner (GP) should receive information on the choice of treatment and the arguments for proposing subcutaneous immunotherapy.

It is recommended that the induction phase be carried out by an experienced allergist as the risk of systemic reactions is highest during this phase. The patient may (in accordance with local regulations) continue maintenance subcutaneous immunotherapy by a GP in close collaboration with the specialist (with the condition that the GP has sufficient training, experience and immediate access to rescue equipment) (see Rescue equipment).

When patients are referred for maintenance treatment in a primary care setting, the GP should confirm that he/she accepts to take the responsibility for the patient. Before referral of the patient, the GP should optimally have received training at the referral clinic in order to ensure a high quality of treatment.

Formalized guidelines for the practical performance of subcutaneous immunotherapy and the recording of injections and side effects (Shuttle Case Record Form) should be forwarded to the GP at the time of referral for maintenance treatment. The clinic initiating subcutaneous immunotherapy should preferably follow up all shared care patients annually. A Shuttle Case Record Form could be used as the communication tool. Termination of treatment before the scheduled date for termination should be reported to the master clinic (including reason for termination).

Diagnostic procedures before initiating subcutaneous immunotherapy.  To ensure ‘effective use of resources’ detailed guidelines for diagnostic procedures (related to disease) to be performed before the start of treatment should be defined.

The IgE-sensitization is assessed by skin testing and/or in vitro determination of serum concentrations of allergen-specific IgE antibodies. Allergen challenge tests may occasionally be indicated in case of uncertainty. Immunotherapy should be considered when positive tests correlate with suspected triggers and the patient's known exposures. Immunotherapy should not be given to patients with negative diagnostic tests or those with positive tests that do not correlate with suspected triggers, clinical symptoms, or exposure (the presence of specific IgE antibodies does not necessarily indicate clinical sensitivity). Clinically relevant exposure to allergens like house dust mites and animal dander might need substantiation by quantifying the actual level in matrasses and furniture to which the patient is exposed.

Information.  The patient should be informed in an objective way of the principles of different treatment options, the clinical efficacy including long-term efficacy, symptom reduction vs disease modifying treatment, duration of treatment, side effects, financial costs and commitment. Information should be both verbal and written and be adapted to the patient's capability to receive and comprehend the information.

Patient education.  Before the start of treatment and continuously during treatment it is appropriate to inform and educate the patient in the principles of the treatment and the monitoring of the treatment. The education should ensure a higher dedication to the treatment and consequently a better compliance (‘high patient satisfaction’). The active understanding of the nature of the disease and the reaction of the body to the treatment will improve the safety (‘minimal patient risk’).

Evaluation of treatment.  Guidelines for evaluation of the treatment and a time schedule for the assessments should be defined. The evaluation includes:

  • Assessment of efficacy and side effects.
  • Criteria for continuing treatment.

Inadequate treatment response, side effects or other conditions resulting in the termination of subcutaneous immunotherapy should be explicitly defined in the Clinical Guidelines.

Practical treatment

Clinical guidelines.  It is recommended to provide clear written instructions for the organization and delegation of competence and responsibility, and all practical procedures:

  • How to handle allergen products.
  • The technique of deep subcutaneous injection, including aspiration and how to handle the occurrence of aspiring blood.
  • Various induction regimens.
  • Safety procedures including procedures for checking of rescue equipment.
  • Defining actual allergen dose based on the preinjection monitoring of the patient.
  • Deciding when to postpone an injection, when to administer a reduced dose or whether not to give increments of the dose.
  • How to calculate doses during exacerbations, during allergen seasons and in case of intercurrent infections and other diseases.
  • How to diagnose and treat local and systemic reactions.

From a legal point of view, adherence to the Clinical Guidelines will place the responsibility for emergencies in the hands of the head of the office, while on the other hand, deviating from the guidelines places the responsibility on the person performing the injections. The use of Patient Immunotherapy Record Forms is recommended for the documentation of patient's status, preinjection monitoring, dosing, postinjection monitoring and for recording any side-effects.

Allergen product.  Patients with multiple allergic sensitivity may be effectively treated with several individual allergen products according to their individual sensitivities. In general this approach is limited to two or at most three allergens, which should be injected at 30-min intervals.

Mixtures of related, cross-reacting allergens, such as a mixture of individual grasses are acceptable provided regulatory demands (stability, etc.) are fulfilled. Another appropriate and widely used example is the mixture of D. pteronyssinus and D. farinae in mite allergen products.

Mixing of unrelated allergens is technically feasible and with the available methodologies, individual allergens can be controlled in the mixture. In view of the potential interactions between enzymatic components, detailed quality control and stability assessments are required (23). A major problem in mixing unrelated allergens is whether optimal doses of individual allergens can be achieved due to the inevitable dilution of individual components. Importantly, the only published controlled immunotherapy trial which evaluated allergen mixtures did not show clinical efficacy. This could have resulted, at least in part, from the failure to reach an optimal dose of individual allergens in the mixture (24).

Transportation, storage and use of allergen products should be in accordance with the recommendations of the manufacturer or alternatively the clinic's own written guidelines. It is recommended to have individualized vials for each patient rather than sharing vials between patients.

The product (allergen, concentration, volume and expiry) date should be double-checked before each injection (‘minimal patient risk’).

Licensed allergen products with proven safety and efficacy should be used whenever possible. However, these products are rarely available in some countries yet, and standardized allergen products (in term of composition and consistency) should be preferred over nonstandardized products. When changing to a new vial a general safety procedure is to reduce the dose or to fractionate the scheduled dose by administering, e.g. half the dose and postpone the remaining dose for 30 min. If no large immediate local reaction or systemic reaction develops, the remaining dose may be administered (3).

Injection technique.  Guidelines for injection technique and anatomical injection sites should be defined. It is recommended to use the outer aspects of the upper arm. Deep subcutaneous injections should be given using a slow injection (injection of 1 ml should take approximately 60 s and aspirations are performed periodically, e.g. every 0.2 ml). It may be advantageous to fix the needle by two fingers in order to prevent movement of the needle. If blood is aspirated, the injection should be terminated, the blood-contaminated product discarded, and the patient observed intensively for 30 min. If no signs of a systemic reaction are obvious, the outstanding amount of the dose may be administered using a fresh product.

Dosage schedules.  The induction regimen may be conducted as conventional ‘one injection per week’, or alternatively as a clustered or rush immunotherapy regimen. Dosage schedules and the amount of allergen to be injected are identical for children and adults. The choice depends on the organization of the service, the disease treated and the patient population. It is essential to explain the rational for selecting a specified induction regimen in terms of efficacy, safety and convenience for the patients. Essentially, the induction regimen represents a compromise between reaching the maintenance dose as fast as possible whilst achieving the highest degree of safety. The schedule is not a fixed proposal and should be adjusted according to the responses of the patient, the time interval between injections, the presence of a co-seasonal allergen exposure etc. The induction regimen will also depend on the choice of either aqueous or depot allergen products.

The maintenance dose is often predefined by the manufacturer, but for some patients it is not possible to reach the recommended top dose (in the range between 5 and 20 μg purified major allergen) (6). The optimal dose is an individualized dose resulting in a high clinical efficacy without any major side effects. In some patients the top dose might be higher than the dose recommended by the manufacturers, based on the clinical response of the patients. Criteria for accepting lower maintenance doses than the standard based on clinical trials should be explicitly defined. For children, in contrast to pharmacotherapy, the doses of allergens for immunotherapy are not necessarily dependent on the age or the weight of the child.

Safety procedures.  Safety procedures should be defined and the responsibility for these procedures unequivocally designated (‘minimal patient risk’). A logbook for the control of emergency equipment with guidelines for the frequency and degree of control might be appropriate.

Regular training in safety procedures and the treatment and observation of anaphylactic reactions should be implemented.

Safety procedures in relation to injections of allergen products are the responsibility of each individual staff member. Unequivocal guidelines should exist for procedures to be performed, monitoring of the patient and questions to be asked before each injection including:

  • Control of adrenaline.
  • Identification of the patient and allergen product.
  • Evaluation of the patient's clinical state.
  • Control of time intervals from the last injection.
  • Recording of reactions at the preceding injection.
  • Control of the allergen product (appearance and expiry date).

Adequate documentation of safety procedures in the ‘Patient Immunotherapy Record Form’ is essential, both for individual patient safety and for medico-legal reasons.

The safe delegation of competence to non-physicians in defining allergen doses (dose modification) requires a high level of training and competence and consultation with the responsible physician in any case of doubt.

Guidelines for the observation of patients after injections including the duration of observation should be defined. As a routine, the patients should be under observation for 30 min after each injection (might be extended in case of systemic reactions and after the treatment of systemic reactions). The patient should be informed not to leave the clinic during the observation period and to immediately inform the staff in case of early symptoms of a systemic reaction. Children should be accompanied by an adult.

Before the patient leaves the clinic the response to the injection must be evaluated and recorded.

Clear written guidelines should be given to patients advising how to respond in case of deterioration of allergic symptoms or the delayed occurrence of symptoms after leaving the clinic.

Dose modification.  Detailed guidelines for omitting an injection, repetition of a previous dose or reduction of a dose should be defined (‘minimal patient risk’) including:

  • The patient's clinical state during the last three days preceding the injection.
  • Time intervals from the preceding injection.
  • Systemic and local reactions following the preceding injection.

Before deciding the dose of allergen, a careful evaluation of the patients’ suitability to receive the scheduled dose represents a crucial step to avoid systemic side-effects. The following guidelines are recommended (6, 25):

  • Postpone injections in patients with airway infections or other significant diseases within the last 3 days.
  • Postpone injections in patients with deterioration of allergy symptoms or increased need for anti-allergic drugs due to recent allergen exposure within the last 3 days.
  • Postpone injections in patients with decreased lung function <80% of personal best value. In asthmatic patients measuring lung function before each injection is mandatory (peak flow is sufficient).
  • Reduce the scheduled dose if the interval between injection sessions has been exceeded. The magnitude of reduction depends on the degree exceeded and should be defined in the Clinical Guidelines.
  • Reduce the scheduled allergen dose in case of a systemic reaction at the preceding visit. The magnitude of reduction depends on the severity of the reaction and should be defined in the Clinical Guidelines. In case of anaphylactic and other life-threatening reactions the continuation of subcutaneous immunotherapy should be carefully evaluated (except in case of Hymenoptera venom allergy, in which it actually reinforces the indication for immunotherapy).
  • Separate allergen injections from other vaccinations for infectious diseases by at least 1 week.
  • Traditionally the late local reaction at the injection site has been used to adjust the allergen dosing at the next allergen administration. Several studies have indicated, that the late local reaction at the preceding injection is not related to a risk of developing a systemic reaction at the next injection (25).

Preinjection monitoring of patients also includes a check of any drug intake that may either increase the risk of systemic side-effects or render the treatment of anaphylactic reactions more difficult. β-blockers are the most important example (26). Heavy beer drinking may similarly increase risk due to inhibition of the histamine-converting enzyme diamine oxidase (27).

Dosing during allergen season.  Dose modification and guidelines for injections during allergen seasons should be clearly defined.

It is recommended not to start induction treatment during allergen seasons.

During allergen seasons injections should not be given if the patient has clinical symptoms (3). As a general safety precaution, a routine reduction in allergen dose during allergen seasons is commonly used, but if the patient is symptom-free the dose does not need to be reduced. In symptomatic patients, the injection should be postponed, symptomatic treatment instituted (intensified), and a reduced allergen dose given when the patient is asymptomatic.

An example of dosage guidelines is given in Appendix I.

Local side effects.  Local swellings commonly occur following injections. In general these swellings are to be expected, are well-tolerated and require no specific therapy.

Subcutaneous nodules are occasionally observed at the location of injections, especially when using aluminium depot products. In most patients they disappear after a period, but in some patient the discomfort necessitates the termination of treatment.

Systemic side effects.  Systemic reactions are any symptoms from organs distant from the location of injection. Systemic side-effects may vary from a few sneezes to fulminate anaphylactic shock and even death. The severity is related to how rapidly the symptoms develop after the injection. Itching in the palms, soles, and on hairy body parts, and rapid onset of erythema and urticaria, rhinitis or asthma occurring within minutes after injection will often progress to anaphylaxis and require treatment without unnecessary delay.

Risk factors for systemic side effects induced by subcutaneous immunotherapy include the presence of asthma, especially uncontrolled asthma (28). The higher frequency of side-effects in asthmatic patients is most likely related to the size of the shock organ (lungs vs upper airways in rhinitics), and a higher degree of airway hyperreactivity. Also the allergen products used most often in asthma are perennial allergens including house-dust mites and pets (cats and dogs), i.e. allergens to which the patient may have recently been exposed before injections. This could induce subclinical asthma which would increase the susceptibility of the patient. Persistent inflammation (29) caused by low grade exposure to perennial allergen might also increase the risk of systemic side-effects.

Systemic reactions are categorized into immediate systemic reactions (occurring within 30 min) and late systemic reactions (debut >30 min after injection). A grading system has been proposed in the EAACI Immunotherapy Position Paper (3). A more operational grading system based on the rate of onset and severity is recommended:

Classification of systemic reactions

  • 0  No symptoms or nonspecific symptoms.
  • I   Mild systemic reactions. Symptoms: Localized urticaria, rhinitis or mild asthma (PF < 20% decrease from baseline).
  • II  Moderate systemic reactions. Symptoms: Slow onset (>15 min) of generalized urticaria and/or moderate asthma (PF < 40% decrease from baseline).
  • III Severe (non-life-threatening) systemic reactions. Symptoms: Rapid onset (<15 min) of generalized urticaria, angioedema, or severe asthma (PF > 40% decrease from baseline).
  • IV Anaphylactic shock. Symptoms: Immediate evoked reaction of itching, flushing, erythema, generalized urticaria, stridor (angioedema), immediate asthma, hypotension etc.

Classifying the reaction, in addition to type and magnitude of reaction, should also include the time of onset following injection and the rate of subsequent development.

Unequivocal guidelines for the treatment of systemic anaphylactic reactions should exist including recommendations for the hospitalization of patients with anaphylactic reactions for observation. An example of the treatment of systemic side effects is given in Appendix II.

Pharmacologic pre-treatment before injections.  Antihistamine pretreatment during the induction phase has shown to reduce the frequency and severity of systemic side effects (30) (Category of evidence Ib). In a controlled trial of Hymenoptera venom immunotherapy involving a small number of patients, antihistamine pretreatment was associated with a better clinical efficacy (31) (category of evidence Ib). Further studies are required. A potential problem is that the use of antihistamine pre-treatment may mask a mild reaction, which would otherwise result in dose modification.

Appropriate guidelines and procedures for checking premedication use are needed.

Documentation.  Guidelines for the recording of the course of the treatment, reactions to injections, side effects and the treatment of side effects should exist. The use of a ‘Patient Immunotherapy Record Form’ might ensure consistency and quality and improve the opportunities for effective and scientific audit (Appendix III).

Audit of systemic reactions.  In the grading of the severity of symptoms the time factor should be incorporated indicating that prompt treatment with adrenaline of these symptoms (and consequently management of the symptoms) should be graded as a Grad IV reaction (anaphylaxis), even if the patient does not progress to develop manifest shock! The response to the treatment is also of importance, e.g. late occurring angioedema or generalized urticaria only requiring minimal treatment is classed as a Grad II reaction.

Paediatric aspects

Indications and contraindications for allergen-specific subcutaneous immunotherapy are the same for children over the age of 5 years as for adults. The specific diagnosis of an IgE-mediated allergic disorder in children, at least in young children, should be performed by a paediatric specialist. Compliance, motivation and co-operation during immunotherapy are especially important when children are treated. Patient education and information is crucial; the language used must fit to the developmental status of the child. The child needs accurate and detailed information about the treatment from the very beginning. It is important to update the child on a regular basis on the progression of treatment. The reason for repeated injections at prolonged intervals during maintenance therapy at times where he/she is asymptomatic should be given. The restrictions on exercise after each injection must be explained and also the reasons for social restriction. It is important to have sufficient time at every visit, so that the child feels safe and relaxed. Compliance with the injection regimen may be affected by age and may be particularly problematic during the adolescent years. Children must always have a parent, guardian or other responsible adult with them at each visit. It is recommended to start immunotherapy as soon as possible in allergic children to modify the natural course of respiratory allergy. Airway remodelling may start early in life, especially in children with severe asthma (32), and ongoing airway inflammation and remodelling in adolescents and young adults may increase the risk of asthma later in life (33). As documented earlier there is evidence that early specific injection immunotherapy reduces the risk of asthma in children with allergic rhinitis (22) and diminishes the risk of new sensitizations in monosensitized children (19, 21).