ALLERGY & HYPERSENSITIVITY

Deurali-Janta Pharmaceuticals Pvt. Ltd.

Asthma

Phr. Asad Kamran

AllergyHypersensitivity

“An important undesirable side effect of immunity is the development, under some conditions, of allergy or other

types of immune hypersensitivity.”

Delayed-Reaction AllergyDelayed-reaction allergy is caused by activated T cells and not by antibodies.

In the case of poison ivy, the toxin of poison ivy in itself does not cause much harm to the tissues. However, on repeated exposure, it does cause the formation of activated helper and cytotoxic T cells.

Then, after subsequent exposure to the poison ivy toxin, within a day or so, the activated T cells diffuse from the circulating blood in large numbers into the skin to respond to the poison ivy toxin.

The damage normally occurs in the tissue area where the instigating antigen is present, such as in the skin in the case of poison ivy, or in the lungs to cause lung edema or asthmatic attacks in the case of some airborne antigens.

Allergic PersonThe allergic tendency is genetically passed from parent to child and is characterized by the presence of large quantities of IgE antibodies in the blood.

These antibodies are called reagins or sensitizing antibodies to distinguish them from the more common IgG antibodies.

When an allergen (defined as an antigen that reacts specifically with a specific type of IgE reagin antibody) enters the body, an allergen-reagin reaction takes place and a subsequent allergic reaction occurs.

A special characteristic of the IgE antibodies (the reagins) is a strong propensity to attach to mast cells and basophils.

Allergic PersonAt any rate, many of the mast cells and basophils rupture; others release special agents immediately or shortly thereafter, including histamine, protease, slowreactingsubstance of anaphylaxis (which is a mixture of toxic leukotrienes), eosinophil chemotactic substance, neutrophilchemotactic substance, heparin, and platelet activating factors.

These substances cause such effects as dilation of the local blood vessels; attraction of eosinophils and neutrophils to the reactive site; increased permeability of the capillaries with loss of fluid into the tissues; and contraction of local smooth muscle cells.

Allergic ReactionsAnaphylaxis

Urticaria

Hay Fever

Asthma

Asthma

The Global BurdenAsthma is now one of the world’s most common long-term conditions, according to the Global Burden of Asthma Report, a comprehensive survey of the prevalence and impact of asthma around the world, based on standardized data collected in epidemiology studies in more than 80 countries.

The disease is estimated to affect as many as 300 million people worldwide-a number that could increase by further 100 million by 2025.

Asthma has become more common in both children & adults around the world in recent decades.

Asthma

Central & Sothern AsiaOver 50 million people in Central & Southern Asia have asthma, and many do not have access to the medications that can control the disease.

Due to rapid industrialization and urbanization throughout the region, the prevalence of asthma is predicted to increase rapidly in the coming years.

Asthma

Age of onset:

1 year in more than 26% of the cases; 1-5 year in 52% of the cases; >5 year in 22% of the cases.

Role of Family history:The incidence of asthma was 18.79% if one of the parents had asthma, 1.65% if one of the siblings had asthma, and 4.12% if the grandparents had the disease.

Asthma

Causes:Viral upper respiratory tract infections: Identified as the triggering factor for asthma among 40% of children.

Seasonal variation: More than one third of the children had attacks of asthma during a specific season. Asthma incidences are more common during winter and rainy season. Only 3% of these episodes occurred during the summer months.

Food items as causal factor: About one fifth of the children seem to suffer from food-related asthma. The most blamed offenders are grapes (57%), bananas (53%) guavas (51%), Citrus fruits (28%), Ice cream (21.5%), fried foods (19%) and tomatoes (12.5%). Peanuts are also a major contributing factor for triggering asthma.

Asthma

Asthma is a clinical syndrome rather than a single disease.

Therefore, grouping asthma into distinctive entities is helpful in developing appropriate management plans.

Although different mechanisms are involved in the pathogenesis of the different types of asthma, all have chronic airway inflammation as the underlying abnormality.

Extrinsic or allergic asthma forms a major portion of adult asthma, & most of the cases are of childhood onset.

Late onset asthma is often caused by sensitization to occupational agents and drugs.

Asthma

Asthma-A Clinical Syndrome

Aspirin & other NSAIDs are the most common causes of drug induced asthma. App. 10%-20% of adult asthmatic patients are sensitive to aspirin. In subjects with asthma, sinusitis, and nasal polyps, aspirin sensitivity increases to 40%.

Patients with brittle asthma are at high risk of dying from asthma.

Those in whom no environmental cause for asthma can be identified are considered to have intrinsic (cryptogenic) asthma. A higher prevalence of intrinsic asthma is noted in female patients.

Asthma

Asthma-A Clinical Syndrome

Different factors trigger asthma exacerbations (attacks) by inducing inflammation or provoking acute bronchoconstriction or both.

Inhaled allergens such as house dust mite, pollen, animal dander, cockroaches and spores of fungi are the most common trigger factors, but ingested or injected allergens can also precipitate acute episodes.

Pollens tend to cause seasonal attacks: tree pollen in spring, grass pollen in summer, & weed pollen in autumn.

Cats & dogs are among the common pets known to trigger the asthma attacks due to allergy to their dander, saliva, urine & feces.

Asthma

Precipitating Factors

Important fungus associated with asthma is Aspergillus fumigates, which causes episodes mainly in late autumn & winter.

Among the respiratory infections, rhinovirus is the common culprit.

Exercise & associated hyperventilation can exacerbate symptoms through changes in temperature of airway mucosa & changes in osmolarity of fluid lining the airway mucosa.

Drugs such as aspirin & other NSAIDs, which induce asthma development, also cause exacerbation.

Asthma

Precipitating Factors

Beta adrenergic blockers provoke bronchoconstriction in asthma patients by blocking Beta receptors to endogenous catecholamines.

Although asthma is not a psychosomatic disorder, emotional stress can cause exacerbation indirectly through hyperventilation.

Factors causing Asthma: Allergen, Viruses, Exercise, Air

Pollution, Cold Air, Foods/Additives, Emotional Stress, Drugs, Occupational factors.

Asthma

Precipitating Factors

Mothers’ anxiety during pregnancy is associated with asthma in their children:

Of particular interest is the possibility that parents’ psychological state could influence the risk of asthma in their children, i.e. the possibility that pregnant women who are stressed, particularly late in the pregnancy, have an increased risk of their child developing asthma.

Although the mechanisms behind the relationship are not understood, it is speculated that increases in a woman’s stress hormone, cortisol, during pregnancy may affect programming of the baby’s adrenal functions or immune development.

Asthma

Asthma in Children

Obese mothers up babies’ asthma attack:

Babies born to overweight mothers are at a greater risk of developing asthma.

Obesity is not a neutral state; adipose tissue is an active producer of pro-inflammatory cytokines, while it also suppresses the action of anti-inflammatory cytokines.

Therefore, obesity is not just a problem of excess fat, but a problem of systemic inflammation.

This may affect the immunological and pulmonary development in the fetus and possibly result in a higher risk of asthma symptoms after birth.

Asthma

Asthma in Children

Researchers found that in children who had at least one asthmatic parent, maternal obesity increased their risk of having asthma at age eight by 65% over children of asthmatic parents whose mothers were not overweight.

Asthma

Asthma in Children

Frequent episodes of wheezing-more than once a month.Activity-induced cough or wheeze.Cough particularly at night during periods without viral infections.Absence of seasonal variation in wheeze.Symptoms that persist after age 3.Symptoms occur or worsen in the presence of:

Aeroallergens (house dust mites, companion animals, cockroach, fungi)ExercisePollen

Asthma

Signs & Symptoms

Respiratory (Viral) InfectionsStrong emotional expressionTobacco smoke

The child’s cold repeatedly “goes to the chest” or take more than 10 days to clear up.Symptoms improve when asthma medication is given.

Asthma

Signs & Symptoms

Severity of asthma is classified into four groups according to symptoms and lung function measurements.Generally patients have poor perception of the severity of their asthma because they tend to adapt their lifestyle to accommodate their Symptoms.This in turn leads to poor control of the disease as well as poor quality of life.Classifying the disease in this stepwise fashion allows the targeting of therapy according to the severity of the disease.

Asthma

Classification of Asthma Severity

Asthma

Classification of Asthma SeverityStep 1

Intermittent

Step 2

Mild Persistent

Step 3

Moderate Persistent

Step 4

Severe Persistent

Intermittent symptoms

once per week

Brief exacerbation (from a

few hours to a few days)

Night-time asthma

Symptoms twice a

month

Asymptomatic & normal

lung function between

exacerbations

PEFR or FEV1: >80%

predicted; variability

20%

Symptoms > once per

week but once per day

Exacerbations may affect

activity and sleep

Night-time asthma

symptoms ≥ twice per

month

PEFR or FEV1: ≥80%

predicted; 20%-30%

variability

Symptoms daily

exacerbations affect

activity and sleep

Night-time asthma

symptoms > once per

week

Daily use of inhaled short

acting Beta 2 agonist

PEFR or FEV1: >60% to

80% predicted: >30%

variability

Continuous symptoms

and frequent

exacerbations

Frequent night-time

asthma symptoms

Physical activities limited

by asthma symptoms

PEFR or FEV1: ≤60%

predicted; >30%

variability.

FEV1: Forced Expiratory Volume

PEFR: Peak Expiratory Flow Rate

Asthma is best described as a chronic disease that involves inflammation of the pulmonary airways and bronchial hyperresponsiveness that results in the clinical expression of a lower airway obstruction that usually is reversible.Bronchial provocation with allergen induces a prompt early phase immunoglobulin E (IgE)-mediated decrease in bronchial airflow (FEV1) followed in many patients by a late phase IgE-mediated reaction with a decrease in bronchial airflow for 4-8 hours.Microscopically, asthma is characterized by the presence of increased numbers of eosinophils, neutrophils, lymphocytes, & plasma cells in the bronchial tissues, bronchial secretions, and mucus.

Asthma

Pathophysiology

Initially, there is recruitment of leukocytes from the bloodstream to the airway by activated CD4 T-Lymphocytes.The activated T-Lymphocytes also direct the release of inflammatory mediators from eosinophils, mast cells, & lymphocytes.In addition, the subclass 2 helper T-lymphocytes subset of activated T-lymphocytes produces interleukin IL-4, IL-5, & IL-13.IL-4 in conjunction with IL-13 signals the switch from IgM to IgE antibodies.

Asthma

Pathophysiology

The cross-linkage of two IgE molecules by allergen causes mast cells to degranulate, releasing histamine, leukotrienes, & other mediators that perpetuate the airway inflammation.IL-5 activates the recruitment and activation of eosinophils.The activated mast cells are eosinophils also generate their cytokines that help to perpetuate the inflammation.Regardless of the triggers of asthma, the repeated cycles of inflammation in the lungs with injury to the pulmonary tissues followed by repair may produce long-term structural changes (“remodeling”) of the airways.

Asthma

Pathophysiology

Asthma is associated with increased expression of inflammatory proteins including cytokines, enzymes, & adhesion molecules.Induction of many of the genes for these proteins is regulated by the transcription factor, nuclear factor-Kappa B (NF-Kappa B).Activation of NF-Kappa B may be the basis for increased expression of many inflammatory genes and for the perpetuation of chronic airway inflammation in asthma.

Asthma

Pathophysiology

Serum Folate Level:higher folate levels were associated with lower total IgE levels, allergic sensitization & wheeze, and lower odds for doctor-diagnosed asthma, despite age, sex, race/ethnicity & economic status.Vitamin D:Low levels of vitamin D could increase the severity of asthma.members with lower Vitamin D levels also tended to have several markers of allergy, such as dust-mite sensitivity.

Asthma

Nutrition & Asthma

Vitamin C:Vitamin C showed significant improvements in respiratory measures and asthma symptoms, including positive effects on pulmonary function tests, bronchoprovocation challenges with methacholine or histamine or allergens, improvement in white blood cell function and motility, and a decrease in respiratory infections.High dose Vitamin C therapy may also help asthmatics by lowering histamine levels.

Asthma

Nutrition & Asthma

Fish Oil supplementation:A possible contributing factor to the increased incidence of asthma may be the consumption of a pro-inflammatory diet.In the typical modern diet, 20-fold to 25-fold more omega (n)-6 polyunsaturated fatty acids (PUFAs) than n-3 PUFAs are consumed, which results in the release of pro-inflammatory AA metabolites.Eicosapentaenoic acid (EPA) & decosahexaenoic acid (DHA) are n-3 PUFAs derived from fish oil that competitively inhibit n-6 PUFA metabolism & thus reduce the generation of pro-inflammatory four-series leukotrienes & two-series prostaglandins & production of cytokines from inflammatory cells.

Asthma

Nutrition & Asthma

Quercetin-The anti-inflammatory bioflavonoid:Quercetin has long been used as a potent natural anti-allergen as it helps to stabilize the histamine-containing mast cells.Quercetin acts by modifying inflammatory signals at the gene level.Inflammatory signals such as TNF alpha, IL-6 and NF-Kappa B were all reduced by Quercetin.Quercetin is high in apples, & to a lesser amount in many fresh fruits.Mothers who ate apples during pregnancy had children with fewer symptoms of asthma.

Asthma

Nutrition & Asthma

Yoga:Yoga is an ancient Hindu discipline that uses postures and breathing techniques (pranayama) to increase the lung airflow, air capacity, stamina & reduces stress.Simple relaxation techniques also help to reduce stress, regulate breathing patterns & also improve lung function.

Asthma

Nutrition & Asthma

Asthma

Management of AsthmaCurrent Therapies Used in Asthma

Bronchodilators Anti-Inflammatory Therapies

Inhaled short acting Beta 2 agonists: Salbutamol &

Terbutaline

Inhaled Corticosteroids: Budesonide, Fluticasone

propionate, Beclomethasone dipropionate & Mometasone

Inhaled long acting Beta 2 agonists: Salmeterol &

Formoterol

Antileukotrienes: Montelukast, Pranlukast

Inhaled Anti-cholinergics: Ipratropium bromide &

Tiotropium bromide

Cromones: Sodium crmoglycate & Nedocromil sodium

Slow release Theophylline, Aminophyline, Doxofylline Anti - Immunoglobin E: Omalizumab

Drugs currently used to treat asthma include Beta 2 agonist, Glucocorticoids, methylxanthines (Theophylline, Doxofylline), cromones & Anticholinergic agents.For acute, severe asthma, the inhaled Beta 2 agonists are the most effective bronchodilators.Short-acting forms give rapid relief, long acting agents provide sustained relief and help nocturnal asthma, & serious side effects are rare when these drugs are used properly.First line therapy for chronic asthma is inhaled Glucocorticoids (ICS), the most potent among currently available agents that reduces airway inflammation.

Asthma

Management of Asthma

Their side effects can be reduced by rinsing the mouth or by using large (volume spacers).Methylxanthines are used both for their anti-inflammatory as well as bronchodilatory actions. Although Theophylline is inexpensive, monitoring its plasma concentrations is both expensive & inconvenient.Doxofylline is a safer alternative to theophylline. Doxofylline is a novel bronchodilator with similar efficacy as theophylline.Doxofylline is preferred in patients with GI intolerance. Doxofylline produces stable serum concentration, hence plasma monitoring is required only in patients with hepatic insufficiency & intolerance to xanthine drugs.

Asthma

Management of Asthma

Cromones work best for patients who have mild asthma; they have few adverse effects, but their activity is brief, so they must be given four times daily.The Anticholinergic bronchodilators are more useful for treating COPD than for chronic asthma. These drugs have virtually no side effects, & their onset is slower & their actions longer than inhaled Beta 2 agonists.The new direction in treating asthma will be medications that have few side effects and is targeted specifically to the pathogenesis of asthma.

Asthma

Management of Asthma

Asad Kamran

Technical Consultant, MPD

Deurali-Janta Pharmaceuticals Pvt. Ltd.