IMMUNOTHERAPY IN ALLERGIC DISEASES

The prevalence of atopic allergic diseases increased substantially towards the end of the 20th century and is set to rise further. Allergic rhino conjunctivitis and asthma are significant causes of chronic illness and health care resource utilization. Highly effective pharmacotherapy are available for control of symptoms in most of the allergic diseases, but these drugs are by no means curative. Over the last two decades, research in basic sciences has elucidated the mechanism underlying allergic inflammation and several experimental approaches have been made to modify the inflammatory process. Specific allergen immunotherapy together with allergen avoidance remains the only measure to modify the natural course of allergic diseases.

Allergen immunotherapy is defined as the “repeated administration of specific allergens to patients with IgE mediated conditions, for the purpose of providing protection against allergic symptoms and inflammatory reactions associated with natural exposure to the allergens”. The history of desensitizing immunotherapy is long - first published in 1911 by Noon and Freeman from St. Mary’s Hospital in London. The first control trial of specific allergen immunotherapy (SIT) was performed by Frankland in 1954.

Mechanism of SIT : In spite of the extensive research, the whole immunological mechanism by which the SIT is effective is not understood. The following points are generally accepted:

1. A shift in the balance between TH1 and TH2 responses on exposure to allergen - the so-called immune deviation.

2. Down - regulation of TH2 response, decreased production of TH2 type cytokines IL4, IL5.

3. Up - regulation of TH1 response, increased production of TH1 type cytokines IL2, IFN1 or IFNgamma.

4. Increase in the production of allergen specific IgG with shift in the balance of IgE: IgG in favour of IgG.

5. Induction of regulatory T cells, which produce IL10 and TGFb and induce allergen specific hypo responsiveness by suppressing both TH1 and TH2 responses.

Indications for Immunotherapy

A. General considerations

1. Demonstration that the disease is due to IgE mediated allergy, either by skin testing with specific IgE in blood.

2. Assessment of allergen exposure: review of local aerobiology and consideration of most relevant allergens in the indoor and outdoor environment of a given patient.

3. Potential severity of the disease to be treated and the number of organs involved.

4. Efficacy of available treatment modalities

5. Patient’s attitude to available treatment modalities

6. Cost and duration of each form of treatment

7. Risk incurred from the allergic diseases and the various forms of treatments.

B. Allergic rhinitis

1. Antihistaminics and topical medications inadequately control symptoms

2. Patients is averse to drug administration or does not desire to receive long terms pharmacotherapy.

3. Pharmacotherapy produces undesirable side effects.

C. Allergic asthma

1. Not severe form of disease (FEV1 > 70%)

2. Symptoms not adequately controlled by allergen avoidance or pharmacotherapy.

3. Both nasal and bronchial symptoms

4. Does not wish to be on long term pharmacotherapy.

5. Pharmacotherapy produces undesirable side effects

Relative contraindications to SIT

1. Secious immunopathologic and immunodeficiency diseases

2. Malignancy

3. Treatment with beta blockers

4. Poor patient compliance

5. Severe asthma uncontrolled by immunotherapy or irreversible airway obstruction

6. Children < 5 years of age

7. Pregnancy: SIT should not be started during pregnancy but can be continued during pregnancy if started earlier

8. Patients with failure of a major organ system

9. Cardiovascular conditions: recent myocardial infarction, unstable angina, uncontrolled hypertension

General precautions during SIT

1. Must be prescribed by specialists and administered by physicians trained to treat severe systemic symptoms

2. High quality and standardized allergen preparations should be used

3. Adjustment of extract dose if anaphylaxis occurs and SIT is to be continued. Possible adjustment can be done if large local reaction occurs with a previous dose.

4. Assessment of patient’s general medical condition before each injection

5. Patient must be instructed to wait for at least 30 minutes after injection.

6. A set procedure must be established by each clinician to avoid possible clinical / nursing error.

Importance of patient education

Patient education is important to ensure compliance and success with SIT. A patient must be informed that:

1. Allergen immunotherapy is long and effects may not be seen for months; in a given patient it may or may not be effective.

2. Symptoms may recur after stoppage of SIT

3. Need for additional pharmacotherapy may be variable

4. Risks and benefits of SIT:

5. Reactions can occur during SIT despite proper attention and without preceding warning signs and symptoms.

Efficacy of SIT

1. SIT has been found to be highly effective and is routinely recommended for hymenoptera venom hypersensitivity

2. Aeroallergen hypersensitivity

a Pollen: Majority of 43 randomised, double blind placebo controlled trials performed between 1980 and 2000 have shown efficacy of SIT in allergic rhinitis due to a number of pollens such as the ragweed, grass pollen, mountain cedar, coconut tree. SIT is also highly effective in pollen induced allergic asthma.

b. Domestic mite: Useful in parennial allergic rhinitis; also in asthma, especially in children.

c. Animal protein allergy

d. Mould: Alternaria, Cladosporium

Efficacy of SIT in bronchial asthma

In a meta-analysis of 20 randomised double blind placebo controlled trials, SIT was found to produce 3 time greater improvement in symptomatology, four time decrease in medication and 7 time decrease in bronchial hyper reactivity. The predicted improvement in FEV1 was 7.1%. SIT has also been shown to prevent progression of rhinoconjunctivitis to asthma. It can also prevent sensitization to new allergens in monosensitized patients. It can decrease use of inhaled corticosteroids, hospitalisation and cost for asthma care.

Routes of immunotherapy

A. Subcutaneous : The most standard route, universally accepted. Various schedules are used:

1. Weekly build up, followed by monthly maintenance

2. Intensive daily build up regimen

3. Rush build up schedule: every 1½ - 2 hours

4. Rapid/rush protocol : every 10-30 minutes

B. Local : Based on application of allergens to various mucous membranes:

1. Nasal immunotherapy : Effective in seasonal allergic rhinitis in adults.

2. Sublingual - swallow immunotherapy : Found to be efficacious against house dust mite and grass pollen allergy in a limited number of studies.

3. Oral and sublingual-spit method immunotherapy have no convincing data in its favour; not recommended currently.

4. Bronchial immunotherapy has unacceptable rate of adverse effects and not recommended.

Duration of immunotherapy

Duration of SIT is decided on a case to case basis. In case of venom immunotherapy. SIT can be discontinued safely after 5 years. In this particular situation, the other criteria used are a negative skin test and undetectable IgE against the venom.

In case of aeroallergens, most authorities recommend 4-5 years therapy. Subjective and objective assessment of clinical efficacy is the only criterion to decide about duration of SIT. Skin tests or IgE estimation are of no use to decide duration of SIT aeroallergen hypersensitivity.

Duration of efficacy of SIT

Most recent studies show lasting effects of SIT. Duration of clinical efficacy of hypo sensitization is directly related to the length of SIT. Efficacy is maintained for 3-6 years, if dose is adequate and treatment time sufficient (3-5 years). when relapse occurs, immunologic memory persists and patient can respond satisfactorily to the new SIT.

Adverse effects of SIT

Local reactions in the form of pain and erythema occur mostly within the first 20-30 minutes. Subcutaneous nodules can form and can be transient or persistent.

Systemic reactions usually occur within the first few minutes, more rarely after 30 min; systemic reactions are more common during the build up phase.

In a large study involving over 400 patients in 1993, local reactions were reported in 10.5% cases, systemic reactions in 4.8% and severe systemic reaction in 0.06% cases. Only 0.37% of doses were associated with the systemic side effects. Deaths have rarely been reported from modern day specific immunotherapy.

Various risk factors identified for systemic reactions from SIT are:

1. Errors in dosage

2. Presence of symptomatic asthma

3. High degree of hypersensitivity as manifested by skin tests of specific IgE measurements

4. Use of beta blockers

5. Injection from a new vial

6. Injections given during periods of exacerbation of symptoms

7. Presence of atopic dermatitis

Conclusion - (WHO Position Statement 1998);

“Allergen immunotherapy is indicated in patients who have demonstrated evidence of specific IgE antibodies to clinically relevant antigens whose allergic symptoms warrant the time and risk of allergen immunotherapy”.

References

WHO position paper. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998; 53(suppl) 1-42.

Dr. Pralay Sarkar, MD., D.M.

Formerly, Senior Resident,

Deptt. of Pulmonary Medicine,

PGIMER, Chandigarh.

ALLERGEN SKIN TESTING

AST determines the degree of inflammatory mediator release due to tissue-fixed specific IgE directed against allergen. The allergy skin test in this context can be viewed as an in vivo test to detect tissue-fixed specific IgE, analogous to in virto tests intended to detect circulating specific IgE.

Clinical applications

AST helps the physician to estimate:

a. the likelihood of an allergic disease being elicited in the patient upon natural or iatrogenic exposure to the allergen.

b. Determine which allergens are indicated for immunotherapy

c which allergens need to be avoided or environmentally controlled.

Techniques of skin testing

1. Epicutaneous : Epicutaneous refers to application of the allergen on the skin surface for example, by means of open or closed patch testing for eliciting contact hypersensitivity. Because the allergen usually does gain access to mast cel ls and basophils through intact skin, this method is not routinely used for detecting immediate hypersensitivity.

2.Percutanous : It refers to application of allergent through the skin surface - for example, by scratching or prick/puncturing the skin. scratch testing is less sensitive and more variable than prick/puncture testing. Prick/puncture testing is the recommended method of screening for immediate hypersensitivity.

3.Intracutaneous : It refers to application of allergen within the topmost layers of the skin.The volume of injection can range from 0.01 to 0.05 ml. Intracutanous testing is the recommended method for confirming that equivocal or absent prick/puncture responses are truly absent.

Reagents for skin testing

In patients with allergic disease, selection of allergens for testing should be based on knowledge of the patient’s environment. Aerobiology may be defined as that branch of biology dealing with the occurrence, transportation, and effects of airborne living organisms or their emanations. The clinical history will provide important clues to etiologically important allergens.

It is useful to segregate allergen exposure into indoor and outdoor varieties since some exposures are exclusively in one setting or the other, and seasonality is primarily an outdoor phenomenon. Outdoor allergens are almost entirely of plant origin, pollen and mold spores, although occasionally large insect exposures, such as caddis fly emanations, may induce inhalant allergy. The major indoor allergens on the other hand, are of animal origin-dust mite, cockroach allergen, fungi and animal dander.

Histamine base, 1.0 mg/ml or 1.8 mg/ml, is FDA-approved as a positive control for percutaneous tests to assess neurovascular reactivity. A negative control containing the diluent used in the allergenic extract (eg. 50% glycerol for percutaneous testing) should be injected to detect dermatographism.

A fixed period of time, 14-20 minutes, is allowed to elapse after allergen administration. The allergic response consists of wheal and erythema. Both wheal and erythema need to be quantitated when measuring percutaneous and intracutaneous skin tests. The longest diameter and the orthogonal diameter, placed at the midpoint of the longest diameter, are measured. Erythema can be measured as precisely as the wheal but is more responsive than the wheal to differing extract doses. The wheal response is less with allergen dose than the erythema response.

Percutaneous erythema response with average diameters>10 mm, regardless of wheal response, are predictive of an increased risk of either asthma or allergic rhinitis in the normal population. In subjects whose erythema cannot be evaluated, wheal diameters > 3 mm have been reported to be associated with an increased prevalence of allergic disease.

There are several grading schemes based on the method of grading the size of the wheal and erythema. The Scandinavian Prick system is suited for dark skinned Indians since it does not take erythema into account. It is based on the number of pluses on the size of the allergen-wheal as a percent of the wheal response with histamine of a certain concentration. Since allergic responses may have similar-size wheals but different-size erythema responses, this approach may yield inaccurate estimates of the allergic response.

Placement of skin tests

The volar surface of the arms and the back are common areas for testing. The back has the advantage of a relatively large uniform area. Its disadvantage is that patients cannot see the allergic response and a tourniquet cannot be used to retard allergen absorption in the event of a systemic reaction. In use of the forearm for skin testing, one should avoid areas most proximal to the wrist or close to the anticubital fossa. Test sites should be placed 4-5 cm from each other to reduce the likelihood of overlap if the allergic response is severe. Since lymphatics drain proximally, potent allergens (such as weed and grass extracts, standardized cat and mite) should be placed proximally rather than distally to avoid proximal drainage of distal inflammatory mediators from influencing upstream reactions.

Safety of Skin Testing

In each patient, the benefits derived from testing should out weight the risks associated with testing. In high-risk patients such as anaphylactically sensitive and/or symptomatic patients, reducing the allergen dose administered can reduce the risk associated with testing. Patients with coexisting cardio respiratory disease who are not expected to tolerate anaphylaxis or anaphylaxis treatment may also require dose reduction. The risk of adverse reaction (malaise, syncope) from percutaneous testing of eighty allergens is 0.04%.

Environmental control measures

The identification and control of triggers of asthma are important steps in nonpharmacological secondary prevention. Once the allergens are identified, avoidance of triggers can prevent exacerbations and reduce symptoms and requirements for medications.

The World Health Organization has recognized domestic mite allergy as a universal health problem and avoidance

of mites may, in the long term,

decrease airway inflammation and hyper -responsiveness. Methods to reduce mite population include appropriate encasement of mattresses, pillows, regular washing of bed linen and blankets in hot water, avoiding carpets, soft toys in home, vacuum cleaning and maintaining a low humidity level by dehumidifiers or air conditioning. Avoiding pets like cat and dog will reduce exposure to animal dander. Pesticide sprays and regular cleaning can control cockroach population. Removing or cleaning mold-laden objects and maintaining a low humidity can best reduce the number of fungal spores.

Dr. Balamugesh T.

MD(Med), DM(Pulm & Critical Care Med.)

Lecturer, Christian Medical College,

Vellore.

SURFACTANT ASSOCIATED PROTEINS

Pulmonary surfactant is a mixture of phospholipids and proteins that subserves myraid biophysical and immunological functions. Surfactant components are secreted by Type II pneumocytes, clara cells and airway submucosal gland cells. The components of surfactant are organized initially into lamellated structures, which in turn form tubular myelin. Tubular myelin forms a monolayer or multi layer at the air water interface of alveoli, thus reducing surface tension from as high as 70 dynes/ cm2 to near zero level. This reduction in surface tension facilitates gas exchange, prevents intrapulmonary arterio-venous shunting and drastically reduces the work of breathing. Surfactant is also required to keep the bronchioles patent. It also aids in translocation of particles from alveoli, thus facilitating mucociliary clearance.

As outlined earlier, surfactant has a role in pulmonary defense mechanism, while its phospholipid components inhibit lymphocyte function, thus decreasing release of immunoglobulins and cytokines; its protein components function as opsonins besides accelerating inflammatory response and release of mediators therein.

Surfactant associated proteins (SP) constitute 5-15% of surfactant. Earlier nomenclature labeled them as apoproteins or glycoproteins but they are now designated as surfactant associated proteins; and belong to 4 subclasses A, B, C and D. The genes encoding these subclasses and their sites of production have also been characterized. SP-A and D, are hydrophilic proteins and play a major role in lung defense mechanisms; whereas SP-B and C are hydrophobic and thus bind to the phospholipids in surfactant. This aids in maintaining the integrity of the surfactant mono - layer.

SP-A : SP-A is a 26 kda protein encoded by a gene on chromosome 10 which is secreted by Type 2 pneumocytes, clara cells and submucosal gland cells. It belongs to the family of collections as it has 3 interlinked domains namely a collagenous domain, a globular domain and a carbohydrate recognizing domain (CRD). The protein exists as octadecamers in tulip shaped configuration. SP-A exerts an autocrine effect in regulation of surfactant secretion. It binds to type 2 cells and increases lysosome uptake from surfactant. It also downregulates phosphatidyl choline secretion from Type 2 cells. Besides, SP-A plays an important role in maintaining the structure of tubular myelin thus enhancing formation of the lipid layer at the airwater interface. SP-A is also instrumental in off-setting the effect of proteins which inactivate surfactant and thus it may form as integral component of commercial surfactant preparations in future.

The immunological functions of SP-A include: an increase in the respiratory burst in macrophages; augmentation of all levels of the inflammatory response including migration, chemotaxis, phagocytosis and release of cytokines and immunoglobulins. The CRO of SP-A binds to LPS of Gram -ve bacteria and cell walls of Gram +ve bacteria. SP-A is believed to promote binding of M.T. to macrophages in patients with HIV infection. It has also been demonstrated that SP-A decreases the allergenic responses induced by house dust mite in asthmatic subjects.

SP-O : This hydrophilic 43 kDA protein is encoded by a gene on chromosome 10. Besides type II pneumocytes and Clara cells, this protein is also secreted by gastric mucosal cells. This protein also belongs to the family of collections and has 2 domains. It is cross shaped; the collagenous domains being connected to trimeric forms of the scobillar domains.

SP-O is the only surfactant associated protein that is present in the aqueous phase of surfactant; thus it subserves no biophysical function. Its non-biophysical functions are responsible for its ability to opsonise micro organisms and acceleration of the inflammatory response.

SP-B : This hydrophobic 8 kDa protein whose gene lies on chromosome 2 is also secreted by type II cells and Clara cells. It exists in a dimeric form and plays a pivotal role in maintaining the surfactant film intact. In concert with SP-C; the positively charged residues of SP-B- interact with negatively charged dipalmitoyl phosphatidyl glycerol - the SP-B-DPPG complexes thus formed are removed from the surfactant monolayer. This increases the concentration of DPPC which is the most surface active interface. It aids in insertion of phospholipid vesicles into a preformed DPPC/DPPG monolayer thus resulting in formation of discoid lipid sheets. SP-B is also a component of tubular myelin.

SP-B deficiency is inherited in an autosomal recessive manner and results in infantile respiratory distress syndrome unresponsive to surfactant administration. The absence of SP-B in these infants deters conversion of pro SP-C to SP-C and hence the former precipitates in alveoli resulting in an alveolar proteinosis like syndrome. SP-B is an important component of commercial surfactant preparation along with SP-C.

SP-C : This SP has molecular weight of 4 kDa and is exclusively secreted by Type 2 pneumocytes. The gene encoding this SP lies on chromosome-8. SP-C is hydrophobic and is found in close association with the phospholipid layer. It exists in 2 forms viz; the palmitoylated form which is more surface active than the depalmitoylated form. Akin to SP-B; SPC increases lipid adsorption to the air water interface and aids in formation of large vesicles and descoid particles which represent the intracellular surface active pool of surfactant. SP-C is also a component of surfactant preparation. Thus surfactant associated proteins play diverse biophysical and immunological roles, despite constituting a miniscule weight of total surfactant; and their deficiency/inactivation has important pathophysiological implications in pulmonary diseases.

Dr. Uma Maheswari K., M.D., D.M.

(Formerly of Department of Pulmonary Medicine,

PGIMER, Chandigarh.)