Immunotherapy For The Treatment Of Asthma

Allergen-specific immunotherapy (SIT) is a desensitization technique for allergic diseases and is in use for a century. Allergen-specific immunotherapy (SIT) offers a curative or a specific mode of treatment. The regimen includes administration of appropriate concentration of specific allergen extracts to which selected patients are allergic. The mechanism involved behind the therapeutic effects of allergen-SIT includes modulation of T-cell & B-cell responses, antibody isotypes, and cells responsible for inflammation such as eosinophils, basophils, and mast cells. Allergen-specific immunotherapy (SIT) works by inducing tolerance in peripheral T-cells. The latter is characterized by the generation of allergen-specific Treg cells, which results in suppression of T-cell proliferation and TH1 and TH2 cytokine responses against the allergen. The results are accompanied by the increase in allergen-specific non-inflammatory antibody isotypes such as IgG4, IgG1, IgA, and a decrease in IgE in the late stage of allergic condition.

Also, decreased the release of mast cells, eosinophils, and basophils promote the effects of therapy. It is how the Allergen-specific immunotherapy (SIT) works to reduce allergies and hence used in treating allergic asthma. [1]

New approaches to the allergen-SIT, such as the use of recombinant proteins, peptides, fragments, and hybrid allergens, have resulted in promising effects but only in the earlier stage of human clinical trials. [1]

GA2LEN/EAACI Pocket Guide For Allergen-Specific Immunotherapy For Treatment Of Allergic Rhinitis and Asthma

Immunotherapy can be administered via different routes such as subcutaneous, sublingual, oral, nasal, bronchial, and lymphatic. But only subcutaneous immunotherapy (SCIT; s.c. injections in the arms) and sublingual immunotherapy (SLIT; allergen kept under the tongue for 1-2 minutes and then swallowed) are in current use. The objective of the existing pocket guide is to provide recommendations for the daily practice of these two specific immunotherapies in allergic rhinoconjunctivitis and asthma. [2]

Recommendations for Immunotherapy For the Treatment of Asthma

Allergen-specific immunotherapy (SIT) is beneficial for patients who approve IgE sensitization to inhalant allergens

Allergen-specific immunotherapy should be considered in patients with moderate/severe intermittent or persistent allergic rhinitis or the particular patients who are not responding to their current pharmacological treatments. SIT can also be used in mild allergic asthma cases by selecting the causative allergen, only if asthma is under control and FEV1 is above 70%

Allergen-specific immunotherapy is strictly contraindicated in patients with uncontrolled and severe asthma (FEV1 under 70%). The restriction also applies to the patients who deny adhering to their medication schedule or non-cooperative ones who cannot understand the pros and cons of the therapy

Studies have given evidence for the efficacy of both (SCIT & SLIT) in the allergic rhinitis

SLIT requires administration of only first dose at the clinic whereas SCIT demands every injection to be given at the place equipped with resuscitation facilities

SIT is a long term treatment and generally requires three years to show the complete cure is achieved. The effects can be seen within 2-3 months of the treatment Symptoms are the only biomarkers to assess the efficacy of the therapy, and hence re-evaluation of clinical signs after every one year is recommended. If clinical responses found are insufficient, patients’ sensitization should be rechecked and proceed accordingly. [2]

Which Patients Are Eligible For Immunotherapy For the Treatment of Asthma?

The principle behind the selection of patients is the IgE sensitization to inhalant allergens. The following allergens have been approved for the treatment in Europe: Birch, Alder, Hazel, Olive, Ash, Grass, Cypress, Parietaria, Ambrosia, Dermatophagoides pteronyssinus and farinae and cat. The other less frequently used allergens still require a proof for their efficacy. However, the physician can start the immunotherapy with the selected allergens by weighing up the pros and cons of it accurately.

Which Patients Are Eligible For Immunotherapy For the Treatment of Asthma?

Note: Allergen-specific immunotherapy (SIT) is recommended for patients above 5 years in age. [2]

How Many Different Sensitizations Can Patients Have To Allow A Successful Monotherapy?

SCIT recommends the individualized approaches. The following practical consideration may help in deciding the regimen of the therapy. A patient with four clinically relevant sensitizations, i.e., cat, dog, olive pollen and grass pollen, the decision for the allergen extract depends on:

  • The allergen responsible for the most extended duration of symptoms in the year
  • The allergen showing maximum severe signs
  • The allergen causing a significant impact on the quality of life
  • The allergen which is more difficult to avoid

In this case, pet allergens can be avoided. Grass pollen has the most prolonged duration of pollen season, whereas, in some regions like South of Spain, olive pollen causes the maximum severity in a quite shorter pollen season.[2]

How Many Allergens Can Be Used In Immunotherapy Simultaneously?

Research has proven that dilution of allergen extract by mixing different unrelated allergens does not benefit in any way. Maximum three different allergens can be combined as per the limits of regulatory bodies. Or else the different vaccines can be administered on alternate days or during the same visit with injecting on left and right arms at an interval of 30 minutes. However, these practices have not been confirmed in clinical trials.[2]

Which Precautions Are Needed To Perform Immunotherapy?

The EAACI standards recommend initiating therapy in the presence of an allergen-SIT specialist. The clinic where the patient is given dosage should be equipped to manage the systemic anaphylactic reactions the minimum risks attached to the therapy. Physicians and nurses should be well trained to Allergen-specific immunotherapy (SIT).

The doctor must educate the patients and their guardians for managing the adverse effects attached to the therapy. [2]

What Are The Long Term Benefits Of Immunotherapy?

SCIT & SLIT are supposed to benefit in the long run even after discontinuation of treatment. The prevention of the development of rhinitis into asthma is one of the primary significance of the therapy. Patients who have received single allergen SCIT may develop immunity against new sensitization, but this outcome still requires robust evidence. [2]

A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients

  1. Objective: The purpose of the double-blind placebo-controlled study in 132 moderate asthmatic patients was to determine the efficacy of immunotherapy with house dust mite extract on symptoms, lung function, medication requirements, BHR and airway passage. [3]
  2. Method: Asthmatic patients aged from 6 to 45 years were recruited for the study from three different urban medical centers of cities Shenyang, Suzhou, Guangzhou, in the People’s Republic of China. Subjects suffering from mild to moderate asthma and had a positive skin prick test (SPT) and specific immunoglobulin E (sIgE) to Dermatophagoides pteronyssinus (Der p) were made part of the research. The selection list of the patient was restricted up to the ones receiving inhaled corticosteroids (ICD) for at least three months, such as budesonide or beclomethasone in dose <500µg/day, or fluticasone in dose <250µg/day. The method involved randomization of 26 and 24 patients into active and placebo treatment groups, respectively. [2]
  3. Objective: The purpose of the double-blind placebo-controlled study in 132 moderate asthmatic patients was to determine the efficacy of immunotherapy with house dust mite extract on symptoms, lung function, medication requirements, BHR and airway passage. [3]

Clinical and Laboratory Evaluations

Selected subjects were screened for SPT against a set of aeroallergens including Der p, fariane (Der f), cat and dog wander, mold mix, American cockroach, grass pollen mix, tree pollen mix, and weed pollen. The response was measured as the mean of the largest diameter of the wheel and its perpendicular diameter and considered positive if the measured response is higher than 3mm.

The severity of the individual patient’s symptoms was recorded as the daily symptom score, which is the sum of daytime and night-time symptom score. Daytime symptom scores were calculated as the mean score of four parameters, i.e., shortness of breath, wheeze, cough, and chest tightness, rating every setting on a score of 0 to 5.

Night-time symptoms were scored from 0 to 4 and calculated as the frequency of nocturnal and early morning awakening by asthma. Also, the medication score is recorded by assigning a rating of 1 to each puff of salbutamol/terbutaline or equivalent dose of oral β2- agonist. The recording of symptoms & medication score was continued during the study procedure.

In addition to these tests, the bronchoprovocation test and PEFR were conducted before and during the procedure. [3]

Treatment

The procedure started with the administration of s.c. Injection to active groups comprising Alutard SQ Der preparation, which is a standardized aluminum hydroxide absorbed Der p vaccine. The initial dose was set as 20 SQ-U, which increased until reached at a dose of 1,00,000 SQ-U. Then, dosing intervals were raised until the end of 26-weeks, and this phase was termed as phase 1(up dosing phase). In phase 2 (maintenance phase), a placebo solution containing 10µg of histamine (comprising 9.8µg of Der p) was administered every 6th week for the next 27 weeks. The dose of inhaled corticosteroids was kept the same during the entire study, but patients were allowed to take rescue medications only when needed. Oral prednisolone at a dose of <40mg/day for no longer than two weeks was allowed in cases of severe exacerbations. However, the use of long-acting β2-agonists and leukotriene receptor antagonists was restricted. [3]

Statistical Analysis

  • SPSS version 11.5 was used to carry out the statistical analysis
  • Student’s t-test for unpaired data was used to measure the differences in symptom and medication scores, PEFR, tIGE, sIGE, ECP and eosinophil count
  • In-between group differences in self-evaluation scores and skin test response were analyzed by Mann-Whitney U-test whereas intra-group differences were analyzed by Wilcoxon test
  • The differences in the rate of adverse reactions were analysed by Chi-square test [3]

Results

  1. Participants: 129 subjects completed the study. Eighty-five patients (44 in SIT group) belonged to the age of fewer than 16 years, whereas 44 patients (20 in SIT group) were of 16 years or more. One patient from the placebo group and two patients from the SIT group dropped out during the study.
  2. Symptoms, Medications, And Self-Evaluation: Symptoms score declined majorly in the first four weeks of the study in both groups: SIT(1.015±0.146 to 0.459±0.076, p<0.001) and placebo (0.925±0.133 to 0.584±0.094, p=0.001). The difference in the scores of the two groups could be measured after 29-32 weeks of therapy when the SIT group started showing significantly lower scores. Then the gap continued to increase with the treatment. Hence, phase 1 did not show any differences in the scores of two groups, but in phase 2 SIT group showed prominent lower scores. Considering the differences in exacerbations where oral prednisolone could be given, no significant difference was measured among the two groups. Forty-eight courses of the oral prednisolone comprising 4710 mg doses were received by 24 subjects in 206 days from the SIT group, whereas 19 patients received 46 courses comprising 4560 mg dose over 223 days.
  3. Bronchial Hyperresponsiveness And Laboratory Parameters: Both the groups showed improvement in skin test response, but at the end of the study, the SIT group showed a significantly lower score (p=0.004). However, the placebo group showed a significant reduction in tIgE, whereas the SIT did not. Also, none of the groups showed changes in sIgE against Der p. [3]

Discussion:

The one year of immunotherapy with Alutard SQ (house dust mite extract) improved the frequency & severity of symptoms and reduced medication use in asthmatic patients. Hence, a more considerable subjective improvement was achieved with the SIT in controlling asthma. However, even after receiving these improvements, the lung function and BHR were less-cut. Besides, the age group did not differ in showing the efficacy of therapy in the maintenance phase, but the placebo group did. [3]

Conclusion:

Allergen-specific immunotherapy (SIT) is the treatment method being used for more than 100 years for the treatment and control of asthma. The therapy works by creating the tolerance in the peripheral T-cells against the specific allergen and hence inhibits the allergic immune responses of the body to inhalant allergens. GA2LEN/EAACI pocket guide describes the guidelines for patients, physicians, and caretakers to perform the SIT. The booklet describes the published recommendations of delivering the therapy, indications & contraindications, no of allergens to be used in the extract, different sensitizations, precautions, and long-run benefits of the treatment. A double-blind placebo-controlled study of house dust mite immunotherapy was performed in Chinese asthmatic patients to confirm the results. The objective of the study was to determine the efficacy of Alutard SQ in symptom reduction, medication use, lung function, BHR, and air passage. The results conveyed significant improvement in symptoms and use of rescue medications reduced. However, the study did not confirm the development in BHR or lung function. Overall immunotherapy proved beneficial for the control & treatment of asthma.

References:

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