VITAMIN E & ALLERGY

Role of Vitamin E in

Allergic Rhinitis and Asthma

Introduction:

Allergic conditions are one of the significant health burdens worldwide. It was reported that about 20-30% people from India suffer from at least one allergic condition. The rising burden of allergic diseases is worrisome because of its increasing prevalence and severity¹. Allergic rhinitis (AR) represents one of the most common allergic conditions across the world and is the most common diseases which usually persist throughout life. The condition affects about 10-25% of people². Prevalence of AR in adults in Europe ranges from 17% to 28.5%. A study from Delhi reported 11.7% prevalence of rhinitis in adult population³. Bronchial asthma (BA) is a common chronic respiratory disease which affects people from all age groups, socio-economic groups, races, countries and both genders.  Over last few years, the prevalence of asthma has increased worldwide. The rates of asthma differ in different countries based on the population studied and methods of diagnosis used. A study from Delhi showed 11.03% prevalence of asthma in adult population. The rate of asthma as well as rhinitis is more in patients with a history of atopy, suggesting a genetic predisposition³. Allergic rhinitis and asthma are closely linked and often coexist^4,5. The relation between allergic rhinitis and asthma is evident from their common etiological and anatomical similarities and therapeutic approach. Allergic rhinitis and asthma are considered as a continuum of inflammatory process of a common air passage^4,6 Asthma is found in15% to 38% of patients with AR, and nasal symptoms are present in 6% to 85% of patients with asthma. AR is a risk factor for asthma, and uncontrolled moderate-to-severe AR affects asthma control. Comorbid asthma with allergic rhinitis increases the risk of disease severity and can have adverse impact on the quality of life of the patient⁴.

Risk factors for allergic rhinitis:

The main risk factor for both AR and asthma is exposure to environmental allergens. It can be indoor allergens or outdoor allergens. These include plant pollens, animal dander, molds and insects. House dust mite is the predominant indoor allergen. Apart from allergens, certain triggers also initiate AR. These include smoking, environmental tobacco smoke, indoor air pollution, exercise, diesel exhaust, psychological factors and cold air⁷. Rapid industrialization, air pollution and changing lifestyles have also contributes to the rising rates of allergic diseases³.

Risk Factors for asthma:

Asthma is considered to be an allergic disorder and the allergic susceptibility of an individual is genetically determined (Atopy). An atopic individual if exposed to an allergen is sensitized and subsequent exposure to the same allergen or trigger may precipitate bronchospasm.

a)      Environmental factors

1)      Indoor and outdoor allergens

2)      Air pollution

3)      Occupational allergens

4)      Respiratory tract infections

5)      Drugs and chemicals

6)      Food allergens

b)      Genetic factors

1)      Family history of asthma or atopy

2)      Presence of other atopic manifestations

3)      Airway hyper responsiveness

4)      Obesity

Important Asthma Triggers

Exposure to various substances that trigger allergies (allergens) and irritants can initiate signs and symptoms of asthma in a sensitized individual. Asthma triggers are different from person to person.

·         Respiratory Infections, usually Viral

·         Allergens( Indoor/Outdoor)

·         Air pollution including smoke and fumes

·         Tobacco smoke ( Active/ Passive)

·         Drugs ( Beta blocker/ NSAIDS)

·         Food additives and preservatives

·         Gastroesophageal reflux disease (GERD),

·         Menstrual cycle in some women

Etiopathogenesis:

Allergic rhinitis is an IgE mediated response resulting in nasal inflammation and symptoms like runny nose, nasal congestion, itching and sneezing. Important cells involved in the pathogenesis of allergic rhinitis include mast cells, eosinophils, Th2 type lymphocytes and basophils. Mast cells upon exposure to antigens cause release of inflammatory mediators like histamine and leukotriene. Basophils also release histamine and leukotrienes.Th2 type lymphocytes release some mediators that attract eosinophils and basophils to the nasal mucosa. Eosinophils release major basic protein, eosinophil cationic proteins and some other inflammatory mediators. The mediators involved in allergic rhinitis include histamine, leukotrienes, cytokines (e.g. Interlukin 4 and 5) and chemokines such as eotaxin and RANTES (regulated upon activation normal T-cell expressed and secreted) ⁶. The pathological process of allergic rhinitis is divided into two phases-sensitization phase and clinical disease phase. In the initial phase of sensitization, allergen exposure results in formation of IgE antibodies. Clinical disease phase characterized by classical symptoms starts after re-exposure to the antigen⁷.

Two important processes involved in the pathogenesis of asthma are inflammation and oxidative damage. Allergic asthma is also associated with hyperresponsiveness of the airways and mucus hypersecretion. The disease is characterized by infiltration by the eosinophils and neutrophils in the lung tissue. Increased production of pro-inflammatory mediators and IgE contributes to the pathological features in asthma. In addition to inflammation, eosinophils and neurtrophils are also the rich source of oxidative stress through the formation of reactive oxygen and nitrogen species⁸.

Interleukin-13, an important cytokine secreted by T helper 2 (Th2) lymphocytes plays significant role in the development of allergic asthma. Interleukin-13 enhances epithelial damage and hyper-responsiveness of airways. Interleukin-13 stimulates release of eotaxin-3 (CCL26) and other eotaxins which are important chemical mediators in the eosinophil recruitment and pathogenesis of asthma. Lung epithelial cells secrete eotaxin in response to T helper 2 cytokines⁹. Classification

Based on severity, allergic rhinitis is classified into mild, and moderate-severe whereas based on the duration, it is classified as intermittent and persistent allergic rhinitis. The older classification of allergic rhinitis was seasonal allergic rhinitis, perennial allergic rhinitis and occupational allergic rhinitis¹⁰. Intermittent allergic rhinitis is defined as symptoms less than four days per week or less than four weeks. If the symptoms are present for more than four days per week and for more than four week, it is termed as persistent allergic rhinitis. If the disease does not hamper sleep, daily activities, sport, leisure, work, school activities and does not cause troublesome symptoms, it is called as mild allergic rhinitis¹¹. Based on the symptoms, patients with allergic rhinitis are also classified into “sneezers and runners” and “blockers”⁷. This classification helps to provide effective treatment based on the symptoms of the patient.

Asthma is classified into four general categories (Table-1):

Table-1: Classification of asthma

Asthma classification	Symptom frequency	Night time symptoms	%FEV1 of predicted	PEF Variability
Mild intermittent	<1 per week	≤2 per month	≥80%	<20%
Mild persistent	>1 per week but <1 per day	>2 per month	≥80%	20–30%
Moderate persistent	Daily	>1 per week	60–80%	>30%
Severe persistent	Daily	Frequent	<60%	>30%

Clinical features

Classical symptoms of AR are nasal itching, sneezing, rhinorrhea, and nasal congestion. Ocular symptoms are also frequent; allergic rhino-conjunctivitis is associated with itching and redness of the eyes and tearing. Other symptoms include itching of the palate, postnasal drip, and cough. AR reduces the quality of life of many patients, impairing sleep quality and cognitive function and causing irritability and fatigue. AR is associated with decreased school and work performance, especially during the peak pollen season.

Allergic rhinitis is generally associated with several comorbidities in children including upper respiratory diseases (eg. sinusitis), lower respiratory disease i.e. asthma, ear problems (e.g. otitis media, eustachian tube dysfunction), eczema, and conjunctivitis⁵.

Allergic rhinitis is often ignored both by the patient as well as clinicians, considering it as a trivial disease; however, it is not true¹. A study among Brazilian adolescents showed that current rhinitis and current rhino-conjunctivitis are associated with high risk of asthma and more severe asthma⁴. Considering the risks associated with allergic rhinitis, evaluation is important for deciding appropriate treatment plan.

Clinical features of asthma include episodic wheeze, chest tightness, nocturnal cough and breathlessness. Children often miss school days. Symptoms starts early in life and may worsen on exposure to allergens or during an upper respiratory infection.

Evaluation and diagnosis

Table 2: Diagnosis of allergic rhinitis and asthma

Allergic rhinitis6

Asthma12

·         Medical history: Family history of atopic disease (e.g. allergic rhinitis or asthma) ·         Symptoms associated with triggers such as change in weather, pet, molds or other allergens ·         Symptoms:  Clear watery discharge from nose, nasal congestion (stuffiness), sneezing, itching of nose and eyes, cough ·         Investigations: ·         Increase in blood eosinophilia ·         Increase in total l serum IgE ·         Skin testing for Aeroallergens ·         Skin testing for food allergens in infants and children

Medical history: Episodic wheeze, breathlessness, chest tightness or cough especially in the night. Family history of asthma or other allergic diseases. Investigations: Lung function tests by spirometry before and after administration of a Beta2 agonist. If post bronchodilator FEV1 increases by 12% and 200ml it is diagnostic of asthma. Peak expiratory flow measurement is a simple test which can be performed in the out patients and it can be used to monitor treatment response also.

Diagnosis of asthma is by a two-step approach. The first step is to suspect the diagnosis and the second step is to confirm the diagnosis. Hence a proper history of episodic wheezing, family history and identification of possible risk factors should be given due credit in suspecting the same.

Spirometry: This test estimates the bronchial obstruction by checking the exhaled air after a deep inspiration.

Peak flow: A peak flow meter is a simple device that measures how hard a patient can breathe out. Lower than usual peak flow readings are a sign of bronchial obstruction.

Lung function tests often are done before and after taking a bronchodilator such as salbutamol, to see the reversibility. If the FEV1 improves by 12% or more in post-test it is diagnostic of asthma.

Other tests include

a)         Allergy testing. This can be performed by skin test or blood test. Allergy tests can identify allergy to pets, dust, mold and pollen. If important allergy triggers are identified, immunotherapy may be a useful adjunct to therapy.

b)         Sputum eosinophils. This test looks for elevated levels of eosinophils in the sputum. Eosinophils are present when symptoms develop and there is airway inflammation.

c)         Provocative testing for exercise and cold-induced asthma. In these tests, precipitation of airway obstruction after a vigorous physical activity or take several breaths of cold air.

Treatment overview:

Environmental control is an important and essential component of the management plan of allergic rhinitis. Allergens and triggers of allergic rhinitis (if known) should be avoided. The pharmacological options for the treatment of allergic rhinitis include oral antihistamines, intranasal antihistamines, decongestants, intranasal cromolyn, leukotriene antagonists and intranasal corticosteroids. The treatment options are selected based on the type and severity of allergic rhinitis. Intranasal corticosteroids are used in patients with moderate to severe persistent allergic rhinitis. In mild persistent allergic rhinitis oral/intranasal antihistamines or leukotriene antagonists are generally preferred. The other options for treatment include specific immunotherapy and anti-IgE therapy (e.g. omalizumab) which are used in very few patients, especially non-responding patients. 

Pharmacotherapy in allergic rhinitis is also associated with some limitations. First generation antihistamines are associated with sedation and anti-cholinergic side effects. Azelastin, a local H1 antihistamine has bitter taste. Intranasal glucocorticoids have minor local adverse events. AIRA Pocket guide Use of alternative and complementary options such as dietary supplement is increasing¹³.

Treatments of asthma

Prevention and long-term control are key in stopping asthma attacks before it starts. Treatment usually involves learning to recognize the triggers, taking steps to avoid them and regular monitoring to make sure that daily asthma medications are keeping symptoms under control.

Medications

The choice of right medications depend on a number of factors, including age, symptoms, asthma triggers and what seems to work best to keep the asthma under control.

Preventive, long-term control medications reduce the inflammation in the airways that leads to symptoms. Quick-relief inhalers (bronchodilators) quickly open swollen airways that are limiting breathing. Long-term asthma control medications, generally taken daily, are the cornerstone of asthma treatment. These medications keep asthma under control on a day-to-day basis and prevent an acute asthma attack.

Types of long-term control medications include:
1) Inhaled corticosteroids. These anti-inflammatory drugs include fluticasone, budesonide, flunisolide, ciclesonide, beclomethasone and mometasone. Controller medications are to be used on a long term basis for their maximum benefit. Unlike oral corticosteroids, these corticosteroid medications have a relatively low risk of side effects and are generally safe for long-term use.
 2)      Leukotriene modifiers. These oral medications including montelukast, zafirlukast and zileuton help relieve asthma symptoms for up to 24 hours. In rare cases, these medications have been linked to psychological reactions, such as agitation, aggression, hallucinations, depression and suicidal thinking.
3)      Long-acting beta agonists. These inhaled medications, which include salmeterol and formoterol, open the airways. When used in combination with an inhaled corticosteroid these drugs these drugs take care of bronchospasm and compliment the anti-inflammatory actions of inhaled corticosteroids.
4)        Theophylline. Theophylline is oral preparations that act as a bronchodilator by relaxing the airway muscles.
5)      Quick-relief (rescue) medications are used as needed for rapid, short-term symptom relief during an asthma attack or before exercise if recommended. Types of quick-relief medications include salbutamol, levosalbutamol and terbutaline. Ipratropium even though used mainly in COPD can also be used to treat asthma attacks.
6)    Oral and intravenous corticosteroids. These medications which include prednisone and methylprednisolone relieve airway inflammation caused by severe asthma. They can cause serious side effects when used for long term, so they're used only on a short-term basis to treat severe asthma symptoms.

Allergy medications:

Allergen immunotherapy. This may help to develop immune tolerance in an individual so that reaction to an allergen when exposed will be blunted.

Omalizumab. This medication, given as an injection every two to four weeks, is specifically for people who have allergies and severe asthma. It acts by altering the immune system.

Bronchial thermoplasty

This treatment is used for severe asthma that doesn't improve with inhaled corticosteroids or other long-term asthma medications.

Bronchial thermoplasty heats the inner layer of the airways with an electrode, reducing the smooth muscle bulk. This limits the ability of the airways to contract, making breathing easier and possibly reducing asthma attacks.

General measures in the treatment of asthma which are applicable to all patients include patient education, avoidance of the trigger factors, environmental control and management of comorbidities. Five-step approach is recommended for the management of stable asthma. Severity and frequency of symptoms guide the treatment choice in asthma¹⁴. Long term use of corticosteroids is associated with several side effects. Similarly, some patients develop resistant to steroids⁸. Despite several options of treatment available, symptoms of asthma in many patients are inadequately controlled. Inadequate response with appropriate dose requires addition of another safer and effective option.

Therapeutic role of vitamin E: Clinical appraisal

Evidence suggests that vitamin E may reduce immune allergic responses and can play role as adjuvant therapy in patients with allergic rhinitis and asthma¹⁵.

Deficiency of vitamin E may be associated with development of asthma and other allergic disorders¹⁶. Plasma α-tocopherol levels are low in adults or children with asthma and it is known that α-tocopherol can reduce inflammation¹⁷. The activities of different isoforms of vitamin E may differ from each other. Some data suggest that α-tocopherol, the anti-inflammatory isoform blocks respiratory hyperreactivity whereas γ-tocopherol is pro-inflammatory and increases the hyperactivity of respiratory system¹⁸. In a mouse model of asthma, lung inflammation in response to house dust mite challenge was reduced with α-tocopherol supplementation whereas γ-tocopherol supplementation caused more inflammation¹⁹.

There is also evidence from the experimental study to suggest the anti-oxidative and anti-inflammatory potential of γ -tocotrienol. In a study, BALB/c mice were sensitized and challenged with house dust mite. The results showed better free radical–neutralizing activity and inhibition of total eosinophil, and neutrophil counts in bronchoalveolar fluid of mouse with house dust mite induced asthma when treated with γ -Tocotrienol. γ -tocotrienol also suppressed methacholine-induced airway hyperresponsiveness in experimental asthma⁸.

Wang and colleagues showed that vitamin E inhibits inerleukin 13-stimulated formation of eotaxin-3 in lung epithelial A549 cells. The relative potency was highest with γ-tocotrienol compared to γ –tocopherol, δ-tocopherol and α-tocopherol. The results of this study suggest that specific vitamin E isoform could be useful as anti-asthmatic agent⁹.

Cook-Mills and colleagues assessed the interaction between plasma levels of two isoforms of vitamin E (α-tocopherol and γ-tocopherol) on the risk of asthma and observed increased risk of asthma in the highest γ-tocopherol tertile with low levels of α-tocopherol whereas protective trend was observed with highest tertile α-tocopherol levels¹⁹. Since α-tocopherol levels are low in asthmatics and since α-tocopherol can reduce inflammation, the investigators feel an increase in α-tocopherol and importantly, a decrease in γ-tocopherol may be beneficial in combination with other regimens to either prevent or improve control of allergic disease/asthma¹⁷

A clinical study among patients with elective tonsillectomy showed that higher vitamin E level is associated with less self-reported allergy. In this study, serum levels of vitamin E, allergen specific IgE level and nasopharyngeal/intratonsilar respiratory viruses were analyzed.  The mRNA expression of several inflammatory mediators in tonsils was analyzed with quantitative RT-PCR. Higher levels of vitamin E were associated with lower rates of self-reported allergy and vice versa. 

These data suggests that vitamin E levels are associated with less allergic disorders¹⁶. There is some evidence from showing protective effect on adult-onset asthma and beneficial effect on FEV1 or wheeze with higher intake of α-tocopherol¹⁸.

Low levels of vitamin E intake by pregnant women may be associated with risk of asthma in the child. The results of a longitudinal study (n=1924) suggested that low intake of vitamin D and E during pregnancy is associated with higher risk of asthma in children during first 10 years of life. Plasma α -tocopherol level at 11 weeks of gestation was associated with increased risk of children receiving treatment for asthma. Similarly, vitamin E intake by mother was associated with increased risk of doctor-diagnosed asthma (OR 0.89, 95% CI 0.81-0.99) during first 10 years in children²⁰.

In a randomized, double blind, placebo controlled clinical trial, Ghaffari and colleagues evaluated effect of vitamin E in 300 children with moderate asthma. The study compared effect of fluticasone plus vitamin E (50 mg/day) versus fluticasone plus placebo. Duration of therapy was eight weeks. Eighty percent children completed the study. FEV1 and FEV1/FVC ratio was significantly better in children receiving vitamin E compared to patients in the placebo arm. Based on the results, the authors concluded that supplementation of vitamin E can improve clinical features and pulmonary functions in children with moderate asthma²¹.  

Vitamin E can be a beneficial addition to the regular treatment in patients with seasonal allergic rhinitis. A randomized, double blind, placebo controlled clinical trial (n=112) evaluated effect of vitamin E 800 mg/day along with the regular treatment of seasonal allergic rhinitis. Patients receiving vitamin E supplementation had lesser nasal symptoms during the day fever season¹⁵.

Conclusion:

Asthma and allergic rhinitis are inter-related to each other with anatomical, patho-physiological and treatment related aspects. Despite several treatment options, response to therapy may be inadequate in some patients. Vitamin E through its antioxidant and anti-inflammatory mechanisms can provide protective effect against these two allergic diseases. Higher levels of vitamin E are associated with lower rates of self-reported allergy and lower levels of inflammatory markers such as interleukin -28 and eotaxins. Vitamin E has promising role as an adjuvant agent in the management of allergic asthma and allergic rhinitis.

References

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