# Allergen Immunotherapy - Subcutaneous and Sublingual

## Principles and Mechanisms of Allergen Immunotherapy (AIT)

### Immunologic Mechanisms

Allergen immunotherapy induces a fundamental reprogramming of the immune response at the allergen-specific level, shifting the dominant paradigm from Th2-driven allergic inflammation toward Th1 and regulatory T cell (Treg) predominance. Central to this process is the induction of allergen-specific regulatory T cells that produce the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta, which collectively dampen Th2 effector responses. In parallel, regulatory B cells (Bregs) are generated that produce interleukin-10 and, critically, generate blocking antibodies that compete with IgE for allergen binding.

The immunoglobulin response to allergen immunotherapy follows a characteristic temporal pattern. In the early phases, total and allergen-specific IgE may transiently increase before gradually declining over the course of years of treatment. The seasonal rise in specific IgE that normally accompanies pollen exposure becomes blunted. Perhaps the most functionally significant humoral change is the robust induction of allergen-specific IgG4, which serves as a blocking antibody by competing with IgE for allergen binding and inhibiting IgE-facilitated allergen presentation to T cells by antigen-presenting cells. Allergen-specific IgA is also induced, contributing to mucosal tolerance. At the cellular effector level, mast cells and basophils undergo functional desensitization, exhibiting reduced mediator release upon allergen exposure. Dendritic cells shift from an inflammatory to a tolerogenic phenotype, reinforcing the regulatory milieu. The ultimate goal of allergen immunotherapy is the induction of sustained immunologic unresponsiveness, or true tolerance, that persists even after treatment is discontinued.

### Clinical Evidence for Disease Modification

Allergen immunotherapy stands alone among available treatments for allergic disease in its capacity to modify the natural history of the allergic march. Clinical studies have demonstrated that children receiving allergen immunotherapy are less likely to develop new allergen sensitizations over time, a benefit not observed with pharmacotherapy alone. The landmark Preventive Allergy Treatment (PAT) study provided compelling evidence that allergen immunotherapy prevents asthma development in children with allergic rhinitis, with 7-year follow-up data demonstrating an odds ratio of 2.52 for asthma development in the control group compared with the immunotherapy group. Furthermore, the sustained nature of immunotherapy's benefit was established by Durham and colleagues in a seminal New England Journal of Medicine publication in 1999, demonstrating that a 3-year course of grass pollen immunotherapy provided clinical benefit lasting at least 3 additional years after treatment discontinuation.

## Subcutaneous Immunotherapy (SCIT)

### Patient Selection

Appropriate patient selection is essential for maximizing the benefit-to-risk ratio of subcutaneous immunotherapy. The fundamental prerequisites include confirmation of IgE-mediated disease with clinically relevant allergen sensitization (meaning the sensitization pattern correlates with the patient's symptom pattern and exposure history) and inadequate symptom control despite appropriate pharmacotherapy and allergen avoidance measures. Accepted indications include allergic rhinoconjunctivitis, allergic asthma that is mild to moderate and well-controlled, and Hymenoptera venom anaphylaxis.

Several contraindications must be considered. Uncontrolled or severe asthma, particularly when FEV1 is below 70 percent of predicted, represents the most important contraindication, as asthma exacerbation is the primary risk factor for fatal reactions to immunotherapy. Significant cardiovascular disease is a relative contraindication. Beta-blocker use is a relative contraindication because beta-blockade increases the risk of refractory anaphylaxis and diminishes the effectiveness of epinephrine rescue. Regarding pregnancy, immunotherapy should not be initiated during pregnancy, but maintenance doses may be continued if they have been previously tolerated without difficulty. Immunodeficiency is a relative contraindication, as the immune dysregulation may blunt the therapeutic response.

### Extract Preparation and Dosing

Allergen immunotherapy extracts are available in both standardized and non-standardized formulations. Standardized extracts, for which potency is measured in bioequivalent allergy units (BAU) or allergy units (AU), are available for cat, dust mite, grass, short ragweed, and Hymenoptera venoms. Most tree pollens, weed pollens, and mold extracts remain non-standardized, with potency expressed in weight per volume (w/v) ratios. Glycerinated extracts use glycerin to stabilize allergenic proteins and extend shelf life, with a maximum concentration of 50 percent glycerin in maintenance vials.

Extract mixing requires careful attention to potential interactions. Proteolytic enzymes present in fungal and cockroach extracts can degrade protein allergens from other sources, reducing their potency over time. For this reason, mold and cockroach extracts should not be mixed in the same vial with pollen allergens. Dust mite extracts also contain proteases that may degrade pollen allergens, and though this interaction is somewhat controversial, common practice is to maintain separate vials for mite and pollen extracts.

### SCIT Protocols

The conventional build-up protocol involves weekly injections of progressively increasing allergen doses over a period of 3 to 6 months until the target maintenance dose is reached. The initial starting dilution is typically 1:1,000 to 1:10,000 volume per volume of the maintenance concentrate, with systematic dose escalation at each visit. The target maintenance dose is defined by effective allergen content rather than arbitrary volume, with established therapeutic targets including 6 to 12 micrograms of Fel d 1 for cat, 7 to 12 micrograms of Der p 1 for dust mite, and 12 micrograms of Amb a 1 for ragweed.

Cluster immunotherapy protocols accelerate the build-up phase by administering multiple injections per visit, reaching maintenance doses in 4 to 8 weeks, though at the cost of a somewhat higher systemic reaction rate. Rush immunotherapy protocols compress the build-up to 1 to 3 days and are primarily used for venom immunotherapy, typically with premedication regimens including cetirizine, montelukast, and in some protocols omalizumab, to reduce the rate of systemic reactions.

During the maintenance phase, injections are administered every 2 to 4 weeks for a total treatment duration of 3 to 5 years. For venom immunotherapy, the standard recommendation is 5 years for most patients, with lifelong treatment advised for patients with a history of near-fatal sting reactions, those with elevated baseline tryptase levels, or those with systemic mastocytosis.

### Safety and Adverse Reactions

Local reactions at the injection site, including erythema and swelling, are common, occurring in more than 50 percent of patients, and are managed with ice application and antihistamines. Large local reactions exceeding 25 mm in diameter, while sometimes concerning to patients and providers, have not been shown to predict subsequent systemic reactions and do not mandate routine dose adjustment.

Systemic reactions occur at an estimated rate of 0.1 to 0.2 percent of injection visits and are graded on a standardized scale.

| Grade | Symptoms | Severity |
|-------|----------|----------|
| 1 | Cutaneous only (pruritus, urticaria, flushing) | Mild |
| 2 | Mild respiratory (rhinitis, throat clearing) or GI symptoms | Moderate |
| 3 | Significant respiratory compromise (wheezing, dyspnea) or prominent GI (vomiting, diarrhea) | Severe |
| 4 | Anaphylaxis with hypotension or respiratory failure | Life-threatening |
| 5 | Fatal | ~1 per 2.5 million injections |

Grade 1 reactions involve cutaneous symptoms only (pruritus, urticaria, flushing). Grade 2 reactions add mild respiratory (rhinitis, throat clearing) or gastrointestinal symptoms. Grade 3 reactions involve significant respiratory compromise (wheezing, dyspnea) or prominent gastrointestinal symptoms (vomiting, diarrhea). Grade 4 reactions constitute anaphylaxis with hypotension or respiratory failure. Grade 5 reactions are fatal, estimated to occur at a rate of approximately 1 per 2.5 million injections.

Risk factors for systemic reactions include uncontrolled asthma, rapid dose escalation protocols, dosing errors, a high degree of allergen sensitivity, and administration during peak pollen season. A mandatory 30-minute observation period after each injection is the standard of care. Dose adjustments are required after a systemic reaction, after a delay exceeding 7 days during the build-up phase, or after a delay exceeding 4 weeks during the maintenance phase.

<image>A dosing schedule chart for subcutaneous immunotherapy comparing conventional, cluster, and rush protocols. X-axis shows time in weeks, Y-axis shows allergen dose (log scale). Conventional protocol: gradually increasing line over 16-24 weeks to maintenance plateau. Cluster protocol: steeper increase with multiple same-day injections (shown as clustered dots) reaching maintenance in 4-8 weeks. Rush protocol: near-vertical increase over 1-3 days with premedication noted. Each protocol has a box showing: number of visits to maintenance, typical duration to maintenance, systemic reaction rate (%), and best indications. Below the chart, a maintenance phase timeline showing 3-5 years of q2-4 week injections.</image>

## Sublingual Immunotherapy (SLIT)

### FDA-Approved SLIT Tablets

| Product | Allergen | Dose | Age Indication | Pre-Season Start | Key Trial |
|---------|----------|------|----------------|-------------------|-----------|
| Grastek | Timothy grass (Phleum pratense) | 2,800 BAU daily | >= 5 years | 12 weeks before season | 25-35% symptom reduction |
| Ragwitek | Short ragweed (Ambrosia artemisiifolia) | 12 Amb a 1 units daily | >= 18 years | 12 weeks before season | Significant symptom reduction |
| Odactra | House dust mite (D. pteronyssinus + D. farinae) | 12 SQ-HDM daily | >= 18 years | Year-round dosing | MITRA trial (asthma benefit) |

Several sublingual immunotherapy tablets have received FDA approval for specific allergen indications. Grastek, containing Timothy grass (Phleum pratense) extract at 2,800 BAU, is approved for daily use in patients aged 5 years and older. It should ideally be initiated 12 weeks before the anticipated grass pollen season, though year-round perennial dosing is also employed. Clinical trials have demonstrated approximately 25 to 35 percent reduction in total combined symptom and medication scores compared with placebo.

Ragwitek, containing short ragweed (Ambrosia artemisiifolia) at 12 Amb a 1 units daily, is approved for adults aged 18 years and older and should similarly be initiated 12 weeks before ragweed season. Odactra, a house dust mite tablet combining Dermatophagoides pteronyssinus and Dermatophagoides farinae at 12 SQ-HDM daily, is approved for adults aged 18 years and older for year-round dosing. Odactra has demonstrated efficacy in both allergic rhinitis and allergic asthma with dust mite sensitization, with the MITRA trial showing significant reduction in asthma exacerbations during a controlled inhaled corticosteroid withdrawal period.

### SLIT Administration

The first dose of any SLIT tablet must be administered in a clinical setting under medical observation for at least 30 minutes to monitor for adverse reactions, including rare anaphylaxis. The tablet is placed under the tongue and held in place for 1 to 2 minutes before being swallowed. All subsequent doses are self-administered at home, and patients must be prescribed an epinephrine auto-injector for emergency use. Doses should be held in the setting of active oral inflammation or wounds, following oral surgery, or during an active asthma exacerbation. Contraindications to SLIT include uncontrolled or severe asthma and eosinophilic esophagitis.

### SLIT Safety Profile

Local oral reactions are the most common adverse effect, occurring in 40 to 75 percent of patients and manifesting as oropharyngeal pruritus, lip or tongue edema, and throat irritation. These reactions are typically self-limited, resolving within the first 1 to 2 weeks of continued treatment without requiring intervention or dose modification. Systemic reactions are substantially rarer than with subcutaneous immunotherapy, occurring at an estimated rate of 0.05 to 0.1 percent of doses, and no fatalities have been reported with FDA-approved SLIT tablets. Anaphylaxis, though rare, has been reported and tends to occur within the first several doses. Gastrointestinal side effects including nausea, abdominal pain, and diarrhea may occur, particularly with liquid SLIT formulations.

### SCIT vs. SLIT Comparison

| Feature | SCIT | SLIT |
|---------|------|------|
| Route | Subcutaneous injection | Sublingual tablet |
| Setting | Clinic only (30-min observation) | First dose in clinic; thereafter home |
| Build-up | Weekly x 3-6 months | None (full dose from start) |
| Maintenance | Every 2-4 weeks | Daily |
| Duration | 3-5 years | 3-5 years |
| Allergens per session | Multiple | Single (per tablet) |
| Systemic reaction rate | 0.1-0.2% per visit | 0.05-0.1% per dose |
| Local reaction rate | >50% (injection site) | 40-75% (oropharyngeal) |
| Efficacy | Possibly superior | Effective (25-35% symptom reduction) |
| Convenience | Lower (clinic visits) | Higher (home-based) |

Direct comparison between subcutaneous and sublingual immunotherapy is limited by a paucity of head-to-head trials, though certain distinctions are clear. SCIT may offer greater overall efficacy based on indirect comparisons, is administered in the office setting with a mandatory observation period, and allows simultaneous treatment of multiple allergen sensitivities. SLIT offers the significant advantage of home administration after the initial supervised dose, carries a more favorable safety profile with lower systemic reaction rates, but requires daily dosing adherence and is currently limited to single-allergen tablets. Cost considerations are complex: SLIT tablets carry higher medication costs, while SCIT incurs greater costs for office visits and administration. Both modalities require 3 to 5 years of treatment for sustained disease-modifying benefit.

<image>A side-by-side comparison infographic of SCIT versus SLIT. Two columns with a central divider. Left column (SCIT): image of injection in deltoid region, bullet points for route (subcutaneous), setting (clinic only), build-up (weekly x 3-6 months), maintenance (q2-4 weeks), duration (3-5 years), allergens (multiple in one session), systemic reaction rate (0.1-0.2% per visit), local reaction rate (50%+), and observation period (30 min). Right column (SLIT): image of tablet under tongue, bullet points for route (sublingual), setting (first dose in clinic, then home), dosing (daily), duration (3-5 years), allergens (single per tablet), systemic reaction rate (0.05-0.1%), local oral reaction rate (40-75%), and observation (first dose only). Center comparison boxes: efficacy (SCIT possibly superior), convenience (SLIT superior), safety (SLIT superior), cost (variable).</image>

## Special Considerations

### Venom Immunotherapy (VIT)

Venom immunotherapy is indicated for patients who have experienced Hymenoptera venom-induced anaphylaxis with confirmed venom-specific IgE sensitization. It is generally not indicated for patients whose reactions were limited to large local reactions or cutaneous-only systemic reactions, though recent guideline updates have expanded consideration of treatment in adults with isolated cutaneous systemic reactions. Available venoms include honeybee, yellow jacket, white-faced hornet, yellow hornet, and wasp (Polistes). Mixed vespid venom provides coverage for yellow jacket and hornets, but Polistes must be added separately if clinically relevant. The target maintenance dose is 100 micrograms per individual venom, or 300 micrograms for mixed vespid preparations.

Venom immunotherapy is remarkably effective, providing 95 to 98 percent protection from systemic reactions upon re-sting, though honeybee immunotherapy is somewhat less effective at approximately 80 to 85 percent protection. The standard duration of treatment is 5 years for most patients, after which therapy can be discontinued with an approximately 5 to 10 percent recurrence rate of systemic reactions over the subsequent 5 to 10 years. Indefinite continuation of venom immunotherapy is recommended for patients with systemic mastocytosis, elevated baseline tryptase levels, a history of near-fatal sting reactions, and possibly honeybee allergy.

### AIT in Children

Allergen immunotherapy can be initiated in children as young as 5 years of age for SLIT tablets according to FDA labeling, while subcutaneous immunotherapy is commonly started at age 4 to 5 years with appropriate precautions. The disease-modifying benefit of immunotherapy is potentially strongest when initiated early in the course of the allergic march, before the full cascade of allergic diseases has developed. The Grazax Asthma Prevention (GAP) study provided important supportive evidence, demonstrating that sublingual immunotherapy with a grass tablet in children with grass pollen allergic rhinitis reduced the subsequent development of asthma over a 2-year treatment period, with benefits sustained at the 5-year follow-up assessment.

### AIT with Biologics

Omalizumab, the anti-IgE monoclonal antibody, has been investigated as an adjunctive therapy during allergen immunotherapy. Pretreatment and concurrent use of omalizumab during the build-up phase of immunotherapy reduces the rate of systemic reactions, offering a strategy for safer dose escalation in high-risk patients. Additionally, there is mechanistic rationale to suggest that omalizumab may enhance the efficacy of immunotherapy by reducing IgE-mediated allergen presentation to T cells, thereby facilitating immune deviation toward tolerance. Omalizumab is used in rush venom immunotherapy protocols for high-risk patients, including those with mastocytosis. However, long-term data on the combined approach remain limited.

## Key Clinical Pearls
- AIT is the only disease-modifying treatment in allergic rhinitis: prevents new sensitizations, reduces asthma risk, and provides sustained benefit after discontinuation
- The target maintenance dose is based on effective allergen content (e.g., 12 mcg Amb a 1), not arbitrary volume
- Do not mix protease-containing extracts (mold, cockroach) with pollen allergens in the same vial
- Large local reactions to SCIT do not predict systemic reactions and do not require automatic dose reduction
- SLIT tablets must have the first dose administered under medical supervision; prescribe epinephrine auto-injector for home use
- Venom immunotherapy provides 95-98% protection from re-sting anaphylaxis; consider lifelong VIT in mastocytosis or near-fatal anaphylaxis
- Beta-blocker use is a relative contraindication to AIT due to increased risk of refractory anaphylaxis (epinephrine resistance)

## References
1. Cox L, et al. Allergen immunotherapy: a practice parameter third update. *J Allergy Clin Immunol*. 2011;127(1 Suppl):S1-S55.
2. Durham SR, et al. Long-term clinical efficacy of grass-pollen immunotherapy. *N Engl J Med*. 1999;341(7):468-475.
3. Virchow JC, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma (MITRA). *JAMA*. 2016;315(16):1715-1725.
4. Golden DBK, et al. Stinging insect hypersensitivity: a practice parameter update 2016. *Ann Allergy Asthma Immunol*. 2017;118(1):28-54.
5. Jacobsen L, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. *Allergy*. 2007;62(8):943-948.