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Efficacy and safety

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

Bronchial immunotherapy

Only two clinical trials have been carried out using this route of administration (1, 2). The results obtained were unimpressive in terms of efficacy and bronchospasm was induced in many of the patients treated. Therefore, this route of administration has been abandoned in view of an unfavourable risk–benefit ratio.

Oral immunotherapy

Although a greater number of clinical trials with a suitable design (3) have been carried out using this route of administration, few of them achieved an acceptable level of clinical efficacy (4, 5). In some trials (6, 7), the effect was no better than that of placebo. Furthermore, adverse events including abdominal pain, vomiting and diarrhoea were recorded in some studies (7, 8). Present results do not support the oral route as an effective alternative.

Nasal immunotherapy

Twenty-two studies of nasally administered immunotherapy have been evaluated (9). Sixteen used a double-blind, placebo-controlled design. Most of these trials demonstrated significant clinical efficacy in allergic rhinitis. Although the results are encouraging, there are other factors to consider as nasal immunotherapy is a treatment for rhinitis only. Some studies reported local adverse effects (10, 11). The only study addressing long-term efficacy demonstrated no sustained effect following discontinuation of treatment (12). There is no data on the possible preventive capacity.

The category of evidence for clinical efficacy is Ib.

Sublingual-swallow immunotherapy

The sublingual route has attracted the greatest interest in recent years, as shown by the number of double-blind, placebo-controlled trials and the fact that sublingual immunotherapy has spread widely in some countries in Europe.

The category of evidence for clinical efficacy is Ia for rhinitis and Ib for asthma.

Further studies are needed to define the most appropriate dosages, the efficacy in paediatric patients, and to evaluate the magnitude of efficacy compared with other available treatments (13–16).

Efficacy and safety.  A meta-analysis published by the Cochrane Library (17) of the clinical efficacy of sublingual immunotherapy in patients with rhinitis included 22 double-blind, placebo-controlled clinical trials, and a total of 979 patients. There was significant heterogeneity for most comparisons, most likely due to the use of several alternative scoring systems in the different studies. Results showed a significant reduction in rhinitis symptoms and medication requirements.

The doses of allergen used in the different studies was analysed by Canonica and Passalacqua (9), and ranged from 3–5 to 375 times the cumulative dose of subcutaneous immunotherapy. There was no clear relation between the dose administered and clinical efficacy, and more dose-response studies are needed to clearly indicate the optimal therapeutic effective dose. A dose–response relationship has been observed for ragweed (18).

The category of evidence for clinical efficacy is ‘Ia’ for birch, Cipress, grasses, olive, Parietaria, D. farinae, D. pteronyssinus. Out of 22 studies 12 include children (<15 years), four studies were conducted exclusively in children (17).

When introducing a new route of administration, safety is a priority, especially when treatment is self-administrated at home (19). Clinical trials and pharmacosurveillance studies have demonstrated a very low rate of systemic adverse effects and no life-threatening systemic side effects (20, 21).

Local side effects have been described in clinical trials. These include itching and swelling of the lips and under the tongue. These effects are more common in studies involving high dosages. In general, these effects are well tolerated, requiring no medication or dosages modifications, and often resolve with continued treatment.

In a few clinical trials systemic reactions such as urticaria and asthma have been observed, all of them self-limiting. Reactions are dose- and allergen-dependent (17).

Therefore, we can conclude that sublingual immunotherapy is well tolerated in both children and adults. However, despite above findings, patients must be warned about the possibility of major systemic or local reactions because this treatment is administered at home, and patients should be informed how to act in the case of such reactions.

Long-term efficacy.  The long-term effect of sublingual immunotherapy was investigated in one open, controlled, observational study included 60 mite sensitive asthmatic children ranging in age from 3 to 17 years (22). Allocation to immunotherapy or pharmacotherapy was based on parental preference. Sublingual immunotherapy was given for 4–5 years and the children followed for 10 years. At 10 years there was a significant reduction in the presence of asthma, use of asthma medication and an increase in PEFR compared with the control group.

Sublingual immunotherapy versus subcutaneous immunotherapy.  There have been studies comparing the two routes of administration, one comparing three groups of patients (sublingual, subcutaneous and placebo) (23) and another using an open design (24), they do not provide sufficient information due to insufficient study design (double-blind, double-dummy).

Two studies have had a double-blind, double-dummy design. The first of these studies (25) showed a reduction in the symptom and medication consumption scores in the group of patients treated with sublingual immunotherapy as well as in the group treated with subcutaneous immunotherapy, with no differences between the two routes of administration. This study had a methodologic limitation because it did not include a third placebo–placebo arm and the sample size was small (10 patients per group).

The other double-blind, double-dummy study (16), investigated patients with birch pollen rhinoconjunctivitis, allocated to three groups and efficacy analysed after 1 year of treatment. A significant difference between the two active groups and the placebo group in terms of symptom load and drug intake was found. However, the numbers studied were inadequate to detect a difference between the two active groups, if one existed. More studies with a greater number of patients are needed to evaluate the magnitude of the clinical efficacy and the optimal dosage.

Indication and contraindications

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

Indications

Immunotherapy is only indicated for confirmed IgE-mediated and clinically relevant disease using standardized products with documented clinical efficacy and safety.

  • Bronchial and oral immunotherapy are not recommended for clinical use.
  • Nasal immunotherapy remains an alternative to the subcutaneous route for adult patients with pollen-induced allergic rhinitis.
  • Sublingual-swallow immunotherapy is indicated in:
  •   Patients with allergic rhinoconjunctivitis and asthma.
  •   Patients sensitive to birch, grasses, cipress, olive, Parietaria and house dust mites.
  •   Patients insufficiently controlled by antiallergic drugs.
  •   Patients with systemic reactions after subcutaneous immunotherapy.
  •   Patients refusing injection immunotherapy.

At present, sublingual immunotherapy is restricted to patients above 5 years of age.

Contraindications

At present contraindications for sublingual immunotherapy should be considered the same as for subcutaneous immunotherapy (3) (see page 6).

Preventive and disease modifying capacity

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

A single randomized controlled open sublingual immunotherapy study in children has shown preventive effect on asthma onset (26). In the control group 18 out of 44 developed asthma vs 8 out of 45 in the sublingual group after 3 years of treatment. Another randomized controlled open study demonstrated the prevention of new sensitizations in a 3-year long trial (27).

The category of evidence for the preventive capacity is Ib.

Practical aspects

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

Precautions

Because this treatment is given to the patient at home, the following precautions should be taken:

  • The patient (for children, their parents) should be given clear, simple written instructions about what to do in the event of an adverse reaction.
  • Allergen tablets and drops should be kept in a secure place out of reach of children.

Administration management and technique

  • Products should be transported, stored, and handled following the instructions of the manufacturer.
  • The product is administered sublingually-swallow, placing it directly under the tongue. For solutions measuring out the dose in a teaspoon and depositing the fluid under the tongue can facilitate this manoeuver.
  • Keep the fluid or tablet under the tongue for 2 or 3 min, and then swallow.
  • It is preferable to administer the product in fasting conditions and, if possible, at the same time every day.
  • Wash hands after using allergen-containing tablets or drops, in order to avoid eye or nasal symptoms due to inadvertent allergen contact.

Treatment schedules and dose modification

The scientific documentation for treatment schedules and dose modifications is limited. Neither the optimal induction regimen nor the optimal top dose is defined. For routine treatment following the guidelines from the manufacturers is sensible.

  • It is advisable to adjust the dose when systemic adverse effects appear.
  • The administration of sublingual immunotherapy must be postponed in the following circumstances:
  • – 
     In the presence of oro-pharyngeal infection.
  • – 
     In the case of major dental surgery.
  • – 
     Acute gastroenteritis.
  • – 
     Exacerbation of the asthma.
  • – 
     PEFR <80% of personal best value.
  • – 
     Simultaneous administration of viral vaccines.

Prevention and treatment of adverse effects

  • Local reactions include itching of the oral mucosa, swelling under the tongue, and gastrointestinal symptoms. In general, these reactions are mild and usually remit spontaneously with no need for treatment. If major discomfort occurs, the treatment should be according to the prescribing specialist.
  • Systemic reactions should be treated as for subcutaneous immunotherapy.

Documentation for patients

Since the treatment is given at home, it is important that the patient has clear, simple instructions on how to proceed if adverse reactions occur. Likewise, the patient should have a logbook to record the administration of treatment, specifying the date of administration, dose administered, and adverse events. This logbook should be evaluated by the specialist at each follow-up visit.

Follow-up and withdrawal from treatment

Monitoring and follow-up of patients under treatment with sublingual immunotherapy aim at verifying the efficacy of the treatment and possible adverse effects and their grade.

It is important that the patient be scheduled for follow-up at least three times a year, since compliance is more difficult to supervise than with subcutaneous immunotherapy, due to home administration of treatment.

Discontinuation of sublingual immunotherapy

  • After a minimum of 3–5 years of administration, the patient is asymptomatic or has mild symptoms for two consecutive years (parallel to subcutaneous).
  • Poor compliance with treatment by the patient.
  • Appearance of any type of contraindication to immunotherapy.
  • Persistent troublesome local side effects.
  • Repeated systemic reactions.
  • Absence of a clinical response to treatment after 2 years.

Paediatric aspects

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

Sublingual-swallow immunotherapy has been suggested to be a particularly attractive treatment for children where safety is paramount and outpatient, home-based therapy is clearly preferable. However, there are few studies in children, and more are urgently required. Several issues remain unsolved: e.g. optimal doses and duration of treatment in children, the evaluation of quality-of-life in children, compliance with home administration, storage of the allergen product during the time family is out of home, e.g. during holidays, dosing during acute but prolonged gastroenteritis etc. The excellent safety profile of sublingual immunotherapy, and the fact that injections are not required with this method raise the possibility that sublingual immunotherapy could be given to children below the age of 5 years, in an attempt to try to modify the natural course of the allergic disease. However, at present this is speculation and definitive trials are required (28, 29).

References

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices
  • 1
    Crimi E, Voltolini S, Troise C, Gianiorio P, Crimi P, Brusasco V et al. Local immunotherapy with Dermatophagoides product in asthma. J Allergy Clin Immunol 1991;87:721728.
  • 2
    Tari MG, Mancino M, Monti G. Immunotherapy by inhalation of allergen in powder in house dust allergic asthma: a double-blind study. J Investig Allergol Clin Immunol 1992;2:5967.
  • 3
    Bousquet J, Lockey RF, Malling H-J (Eds). WHO Position Paper. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998;53(Suppl. 44):142.
  • 4
    Moller C, Dreborg S, Lanner A, Bjorksten B. Oral immunotherapy in children with rhinoconjunctivitis due to birch pollen allergy. Allergy 1986;41:271279.
  • 5
    Giovane AL, Bardare M, Passalacqua G, Ruffoni S, Scordamaglia A, Ghezzi E et al. A three-year double-blind placebo-controlled study with specific oral immunotherapy to Dermatophagoides: evidence of safety and efficacy in paediatric patients. Clin Exp Allergy 1994;24:5359.
  • 6
    Cooper PJ, Darbyshire J, Nunn AJ, Warner JO. A controlled trial of oral hyposensitization in pollen asthma and rhinitis in children. Clin Allergy 1984;14:541550.
  • 7
    Oppenheimer J, Areson JG, Nelson HS. Safety and efficacy of oral immunotherapy with standardized cat product. J Allergy Clin Immunol 1994;93:6167.
  • 8
    Mosbech H, Dreborg S, Madsen F, Ohlsson H, Stahl Skov P, Taudorf E et al. High dose grass pollen tablets used for hyposensitization in hay fever patients. A one-year double blind placebo-controlled study. Allergy 1987;42:451455.
  • 9
    Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol 2003;111:437448.
  • 10
    Nickelsen JA, Goldstein S, Mueller U, Wypych J, Reisman RE, Arbesman CE. Local intranasal immunotherapy for ragweed allergic rhinitis: clinical response. J Allergy Clin Immunol 1981;68:3340.
  • 11
    Welsh PW, Butterfield JH, Yunginger JM, Agarwal MK, Gjeich GJ. Allergen-controlled study of intranasal immunotherapy for ragweed hay fever. J Allergy Clin Immunol 1983;71:454460.
  • 12
    Passalacqua G, Albano M, Pronzato C, Riccio AM, Scordamaglia A, Falagiani P et al. Long-term follow-up of nasal immunotherapy to Parietaria: clinical and local immunological effects. Clin Exp Allergy 1997;27:904908.
  • 13
    Brown JL, Frew AJ. The efficacy of oromucosal immunotherapy in respiratory allergy. Clin Exp Allergy 2001;31:810.
  • 14
    Malling HJ. Is sublingual immunotherapy clinically effective? Curr Opin Allergy Clin Immunol 2002;2:523531.
  • 15
    Nelson HS. Advances in upper airway disease and allergen immunotherapy. J Allergy Clin Immunol 2003;111:0s793-s798.
  • 16
    Khinchi MS, Poulsen LK, Carat F, André C, Hansen AB, Malling H-J. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004;59:4553.
  • 17
    Wilson DR, Torres  Lima M, Durham SE. Sublingual immunotherapy for allergic rhinitis: systemic review and meta-analysis. Allergy 2005;60:412.
  • 18
    André C, Perrin-Fayolle M, Grosclaude M, Couturier P, Basset D, Cornillon J et al. A double-blind placebo-controlled evaluation of sublingual immunotherapy with a standardized ragweed product in patients with seasonal rhinitis. Evidence for a dose–response relationship. Int Arch Allergy Immunol 2003;131:111118.
  • 19
    Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108:S147336.
  • 20
    Grosclaude M, Bouillot P, Alt R, Leynadier F, Scheinmann P, Rufin P et al. Safety of various dosage regimens during induction of sublingual immunotherapy. A preliminary study. Int Arch Allergy Immunol 2002;129:248253.
  • 21
    Lombardi C, Giargioni S, Melchiorre A, Tiri A, Falagiani P, Canonica GW et al. Safety of sublingual immunotherapy with monomeric allergoid in adults: multicenter post-marketing surveillance study. Allergy 2001;56:989992.
  • 22
    Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F, Sensi L et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy 2003;33:206210.
  • 23
    Mungan D, Misirligil Z, Gürbüz L. Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite-sensitive patients with rhinitis and asthma – a placebo controlled study. Ann Allergy Asthma Immunol 1999;82:485490.
  • 24
    Bernardis P, Agnoletto M, Puccinelli P, Parmiani S, Pozzan M. Injective versus sublingual immunotherapy in Alternaria tenuis allergic patients. J Invest Allergol Clin Immunol 1996;6:5562.
  • 25
    Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F. Sublingual versus injective immunotherapy in grass pollen allergic patients: a double-blind, (double-dummy) study. Clin Exp Allergy 1996;26:12531261.
  • 26
    Novembre E, Galli E, Landi F, Gaffarelli C, Pifferi M, De Marco E et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004;114:851857.
  • 27
    Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real-life: clinical efficacy and more. Allergy 2004;59:12051210.
  • 28
    Scheinmann P, Ponvert C, Rufin P, De Blic J. Immunotherapy in young children. In: LockeyRF, BukantzSC, BousquetJ, editors. Allergens and allergen immunotherapy. New York: Marcel Dekker, 2004:567583.
  • 29
    Sopo SM, Macchiaiolo M, Zorzi G, Tripodi S. Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature. Arch Dis Child 2004;89:620624.

Appendices

  1. Top of page
  2. Efficacy and safety
  3. Indication and contraindications
  4. Preventive and disease modifying capacity
  5. Practical aspects
  6. Paediatric aspects
  7. References
  8. Appendices

Appendix I

Example of dosing guidelines:
Table 1. Dose guidelines subcutaneous immunotherapy induction phase
Omit injection in case of(a) infection in airways or other disease during the last 3 days
 (b) deterioration of allergic symptoms or increased needs for drugs during the last 3 days
 (c) peak flow <80% of individual best value
Terminate treatment session(a) local immediate reaction >5 cm
 (b) systemic reaction
Injection interval2 weeks [RIGHTWARDS DOUBLE ARROW] dose escalation according to schedule
 2–4 weeks [RIGHTWARDS DOUBLE ARROW] repeat preceding dosing
 4–6 weeks [RIGHTWARDS DOUBLE ARROW] dose reduction 1 step
 6–8 weeks [RIGHTWARDS DOUBLE ARROW] dose reduction 2 steps
 ≥8 weeks [RIGHTWARDS DOUBLE ARROW] treatment reinstituted
Local immediate reaction at preceding injection (30 min)<5 cm [RIGHTWARDS DOUBLE ARROW] dose escalation according to schedule
 5–8 cm  [RIGHTWARDS DOUBLE ARROW] repeat preceding dosing
 >8 cm [RIGHTWARDS DOUBLE ARROW] dose reduction 1 step
Local delayed reaction at preceding injection (1st day)repeat preceding dose if the reaction has been inconvenient for the patient
Mild systemic reaction at preceding injection (mild urticaria, rhinitis, asthma)dose reduction 1–2 steps
Severe systemic reactionConferring on continuous treatment
Dose guidelines maintenance treatment
Definition of maintenance dose(a) the optimal dose defined from clinical studies
 (b) the individual optimal dose (based on patient response)
Intervals between injections at shift to maintenance treatment2 weeks (max. 3 weeks) [RIGHTWARDS DOUBLE ARROW]
 4 weeks (max. 5 weeks) [RIGHTWARDS DOUBLE ARROW]
 8 weeks (max.10 weeks) maintenance treatment
Dose modifications maintenance treatment
Omit injection in case of(a) infection in airways or other disease during the last 3 days
 (b) deteriorations of allergic symptoms or increased need for drugs during the last 3 days
 (c) peak flow <80% of normal value
Injection intervals in maintenance treatment≤10 weeks [RIGHTWARDS DOUBLE ARROW] unchanged dosing
 10–12 weeks [RIGHTWARDS DOUBLE ARROW] dose reduction 20%
 12–16 weeks [RIGHTWARDS DOUBLE ARROW]  - ‘‘ - 40%l
 ≥16 weeks [RIGHTWARDS DOUBLE ARROW] treatment reinstituted
Local immediate reaction at preceding injection (30 min)<8 cm [RIGHTWARDS DOUBLE ARROW] unchanged dosing
 >8 cm [RIGHTWARDS DOUBLE ARROW] dose reduction 20%
Local delayed reaction at preceding injection (1st day)Dose reduction 20% if the reaction has been inconvenient for the patient
Mild systemic reactionDose reduction 20–40%
Severe systemic reactionConferring on continuous treatment
Dose increases after reduction of maintenance dose≤20% [RIGHTWARDS DOUBLE ARROW] full dose after 4 weeks and then after 8 weeks
 >20%  [RIGHTWARDS DOUBLE ARROW]  weekly inj. to maintenance, then 2–4–8 weeks

Appendix II

Example:
Table 2. Treatment of side effects in adult patients
Large local reaction (>12 cm after 30 min)Antihistamine orally
 Observe for minimum 60 min
RhinitisAntihistamine orally
 Observe for minimum 60 min and repeat peak flow
Mild urticariaAntihistamine orally
 Observe for minimum 60 min
Asthmaβ-2 agonist inhalation
 β-2-agonist i.v./s.c.
 Oxygen
 Corticosteroids (Prednisolone 50 mg or Methylprednisolone 40 mg i.v.
 Consider hospitalization
Systemic reactionsAdrenaline (1 mg/ml) 0.3–0.5 mg deeply i.m.
Generalized urticaria, angioedemai.v. line (saline)
 Check blood pressure and pulse rates
 Antihistamine clemastine (1 mg/ml) 1–2 ml (1–2 mg) i.m.
 Corticosteroids (prednisolone 50 mg or methylprednisolone 40 mg i.v.
 Consider hospitalization
Anaphylactic shockAdrenaline (1 mg/ml) 0.5–0.8 mg deeply i.m.or (diluted 0.1 mg/ml) 0.3–0.5 mg i.v. (slowly in fractionated doses) may be repeated after 10–20 min
 i.v. line (saline)
 Place patient in supine position
 Oxygen 5–10 l/min
 Check blood pressure, pulse rate, and oxygen saturation
 Antihistamine Clemastine (1 mg/ml) 1–2 ml (1–2 mg) i.v.
 Methylprednisolone 80 mg i.v.
 Hospitalization necessary because of the risk of delayed shock
Doses for childrenAdrenaline (1 mg/ml) 0.01 mg/kg (0.01 ml/kg) i.m. If needed (diluted 0.1 mg/ml) i.v.
 Antihistamine Clemastine (1 mg/ml) 0.0125–0.025 mg/kg i.m.
 Corticosteroid Methylprednisolone 2 mg/kg i.v.

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