RESURGENCE OF TUBERCULOSIS

DOTS FAILURE OR THOUGHT FAILURE!

Ravindran Chetambath

Professor & Head

DM Wayanad Institute of Medical Sciences

Wayanad, Kerala

Abstract

India implemented the Revised National TB Control Program (RNTCP) as a national government run system that used a thrice weekly regimen administered by DOT. Cure rates in India have been comparable with countries using daily dosing. At the same time Multidrug resistance and Extensive drug resistance were reported from many parts of the country. This prompted reconsideration of the existing program and introduction of daily regimen in place of intermittent regimen. When a new program is being implemented it is important that we should take stock of the defects of previous program leading to its failure and try to correct them.

Key Words

Revised National Tuberculosis Control Program, Directly observed short course, Multidrug Resistance, Daily regimen

Introduction

The World Health Organization (WHO) declared tuberculosis (TB) a global public health emergency in 1993 and since then intensified its efforts to control the disease worldwide¹. Revised National Tuberculosis Control Programme (RNTCP) and directly observed treatment short course (DOTS) were introduced in the country after a pilot study in 1997. The programme was introduced in a phased manner covering the whole population of the country by 2006.It enjoyed the back up of infrastructure of health care system, a new hierarchal human resource chain and huge external funding. The concept of daily, directly observed therapy, incorporating a full six months of Rifampicin has been adopted by the majority of countries worldwide as a major part of Stop TB Strategy². Lower rates of cure in National TB Control program (NTP) highlight the operational challenges of delivering a daily regimen over an extended period of  time^{2, 3}. India implemented the Revised National TB Control Program (RNTCP) as a national government run system that used a thrice weekly regimen administered by DOT⁴. Cure rates in India have been comparable with countries using daily dosing. TB mortality has dropped significantly, and the prevalence of TB has declined slightly over the last two decades⁴. The therapeutic regimens given under direct observation as recommended by WHO have been shown to be highly effective for both preventing and treating TB ⁵. It was propagated with much fanfare and enthusiasm and even the protagonists became ardent believers by the course of time. It took 30 years for the national tuberculosis control program to be declared a failure, but it took only 10 years or less to say that RNTCP is not achieving the desired result. Now the revised program is being re-revised citing examples of multidrug resistance and extensive drug resistance.

Directly observed therapy short course

Directly observed therapy short course (DOTS) is the internationally recommended strategy to ensure cure of tuberculosis. It has become the standard for the diagnosis, treatment and monitoring of tuberculosis worldwide and has been implemented in 182 of 211 countries, covering more than 77% of world's population^6,7 in response to the growing threat of this disease. 

In India, under the Revised National Tuberculosis Control Program (RNTCP), the percentage of smear-positive re-treatment cases out of all smear-positive cases is 24%⁸. The causes of re-treatment include relapse, failure, and default in treatment. RNTCP does not follow up the patients for any period of time after successful completion of treatment to determine whether they relapse. Due to the fact that India has the maximum number of cases and highest burden of TB in the world, an effective TB control program in India is essential. It also will have global implications in the international TB control effort. There is no statistically significant difference between the two treatment groups in terms of cure or treatment completion. Hill categorically admits that superiority of DOTS over unsupervised therapy for routine TB care has not yet been shown in an evidence-based fashion⁹. His contention is that it is not better in suboptimal settings and indicates that the program quality must be strong enough to yield its optimal benefits.  Of the new smear-positive patients registered under Category 1, the default and failure rates were 12% and 5%, respectively, reported by Chandrasekaran in 2006 and 16% and 4%, respectively, reported by Thomas¹⁰. Mehra recorded a failure rate of 3.4%¹¹. The distribution of default and failure cases in Category 2 patients was 22% and 14%, respectively, in the study by Mukherjee¹².  Hill in his review of studies from around the world, calculated an average failure rate to be 2.4% ±2.2% for 21 culture-based studies and 2.5% ±1.7% for nine smear-based studies⁹. Nevertheless, high relapse rate of 11-13% has been reported in patients treated by DOT under RNTCP from several different locations in India over the last many years ^{10, 13, 14}.

Most authorities are convinced that DOTS improves treatment effectiveness, drug resistance rates, and overall TB control. It is a fact that the intermittent regimen used under the program is equally effective under direct observation as compared to the daily regimen, and choosing a daily regimen does not undermine the successes of the program ^{15, 16}. There are no good quality studies that may cast light over the preferences, adherence, and felt problems of the clients of the RNTCP. Without understanding the wishes and the problems seen from the patients, it may be difficult to modify a strategy so strongly advocated by the WHO and many other international organizations working with TB. Role of HIV, Multi Drug Resistant (MDR) TB, re-infection with a different strain of Mycobacterium tuberculosis and outcomes in the pediatric age group, also need to be investigated for relapse. However, based on the above evidences and in the interest of having uniformity of care across all healthcare sectors it is decided to introduce daily regimen under RNTCP. It is argued that this will help to achieve universal access to quality TB care and prevent development of drug resistance. When such a decision is taken and program is being reintroduced, it will be better to take stock of what went wrong in the previous programs. It will help the program managers to take corrective steps so that the new program will not have the same fate after a few years.

Reasons for Failure

The three main causes of failure of TB treatment relate to the actions of doctors in prescribing incorrect regimes, problems with the drugs being delivered (either the quantity or the quality), and the patients failing to take sufficient quantity of the drugs.

I.                   Doctors – Not adhering to guidelines or following inappropriate guidelines.

II.                Drugs –Poor quality, irregular supply and wrong delivery (dose/combination). In some case drugs are unsuitable due to the presence of drug resistance.

III.             Patients –Lack of information, Lack of money for treatment and/or transport, fear of actual or presumed side effects, lack of commitment to a long course of drugs and other co morbidity.

Apart from the above we have to consider few other reasons for the program failure. This is because system did not correct certain inherent causes of failure of the previous program (NTP).

1)      Administrative failure

The initial enthusiasm once the program was launched faded away too quickly. There was lack of commitment on the part of administrators. Most of the program managers and contractual staff were committed and RNTCP gained a lot of ground among common man due to their hard work. Most of the medical college faculty who were suspicious initially cooperated and it was bringing good result. This was mainly due to the concerted effort of program managers, District TB officers, medical college core committee members and contractual staff. But after few years these staff were shuffled and their grievances were never attended. Contractual staff on meager wages struggled to get that amount released in time. District program managers of NHM were responsible for dealing finances. Since they have many other programs to look after, due importance to TB program was never given. Once commitment is lost and enthusiastic workers left for greener pastures we can imagine the fate of the program.

Treatment adherence is a critical determinant of treatment outcomes. Poor outcome and emergence of drug resistance are mainly due to irregular and incomplete treatment. The DOTS strategy has been the backbone of TB programs for the last decade. In certain places, strict adherence to the program by healthcare worker has resulted in cost-effective and sustainable control of TB epidemics. However, accumulating evidence has pointed to the effectiveness of a wide variety of approaches including community and family-centered DOTS, which is more achievable for most developing healthcare systems and produce comparable outcomes to healthcare worker supervised DOTS.

However in a larger perspective, treatment support system developed with mutual trust and respect between the patient, family, providers, treatment supporters and the health system. This will promptly identify and address all possible factors that could lead to treatment interruptions. This includes not only medical factors such as co-morbidities, adverse drug reactions and emergencies, but also take care of various social, vocational, nutritional, economic and psychological stress experienced by the patient throughout the course of treatment. Regular and effective supervision by the health supervisors at various levels and close monitoring of the progress made by the patient on treatment are critical components to ensure high standards of care. Capacity building among health care workers and engaging local community based organizations, self-help groups and patient support groups could prove to be effective interventions to promote treatment adherence ^{17, 18}. Supervision and support should be individualized and should include a range of recommended interventions including patient counseling and education. An important element of the patient centered strategy is to assess and promote adherence to the treatment regimen, and, to address poor adherence when it occurs. These measures should be tailored based on the patient's clinical and social history. It also should be mutually acceptable to the patient and the provider.

2)      Role of private practitioners

India continues to have high TB incidence, and, the mortality due to TB is still unacceptably high. The challenges of TB control in India are magnified by the existence of parallel systems for TB diagnosis and treatment – the public and the private. Each system takes care of approximately half of the TB cases¹⁹.The methods and standards vary greatly depending on whether public or private care is accessed and furthermore what type of private care is sought, from super-specialty tertiary institutions to non-qualified providers ²⁰. RNTCP was implemented through the existing health care system, the pivotal role being played by district TB centers. There were additional staff supplement with adequate materials and funds. Every peripheral health center is empowered to take up the challenge of diagnosing, treating and monitoring TB patients. Since medical colleges are the opinion leaders in health care and trains new generation of doctors and paramedics there was an attempt to bring all medical colleges in the loop and hence task force is being organized in public and private medical education institutions. At the same time we are all aware that 50-60% of health care delivery in the country is through private practitioners. They work in institutions as well as individually. RNTCP, to a large extent, failed to bring these practitioners in to its fold. There were many concerns for them which were not addressed properly. Hence treatment of tuberculosis through private practitioners remained largely out of the program. Many institutions do not want to join a Govt. run program for fear of auditing. But most important of all is the fear of exposing their know how in treating tuberculosis. I know many practitioners using non rifampicin containing regimen, non-pyrazinamide containing regimen and levofloxacin based first line treatment. Many have more concern on liver dysfunction, peripheral neuropathy etc. and hence load the patient with two or more vitamins. This will all lead to non-compliance. Once therapeutic response is poor these patients are referred to the program. This previous treatment history is also poorly documented and may be a source of bias. It has been recorded that patients turn up at RNTCP after seeking medical care from many providers in the private sector. It might be true that many TB patients may see an advantage in not reporting previous treatment, in order to escape with a lighter 6-month treatment instead of a more punishing 8-month treatment regimen. When drug resistance is being reported from many parts of the country, these same practitioners started blaming the program.

3)      Availability of drugs in the open market

When the Govt. is committed to provide good quality anti TB drugs to patients in the country, why the drugs were made available in the open market? When these potent drugs are freely available, there is a chance to misuse these drugs to the extent of treating with inadequate regimen, inadequate dosing etc. This will lead on to failure and development of resistance. If it was banned when RNTCP was expanded to cover the whole nation, all the patients (suspected or diagnosed) will be brought to the single window of DOTS. This will ensure uniform treatment, treatment completion and follow up.

4)      Overemphasis on sputum microscopy and neglecting clinical and radiological evidence.

In NTP the main disadvantage being pointed out is overemphasis on radiology. X ray being highly sensitive but poorly specific, leads to more of false positives. When we turned to RNTCP the emphasis shifted to sputum microscopy. This is a highly specific test even though sensitivity is poor. So we have a proportion of false negatives in the society. Actually the planners should have developed a more realistic diagnostic test combining both. In the recent guidelines a new entity is included as clinically diagnosed TB which is diagnosed through clinical and radiological methods. Overdependence of sputum microscopy led to a peculiar situation in which clinicians failed to use their clinical judgment but blindly followed sputum microscopy result. Even after improvement in staining and detection, the sputum pick up remained as low as 60%. So 40% of TB cases roam around without being detected. When these patients are reported as negative after repeated sputum examination, there is hesitancy in starting anti-TB drugs. This leads to delay in starting treatment and progression of disease.

Conclusion

Urgent efforts are necessary for the control of tuberculosis in the country. Both intermittent and daily regimens are proved to be effective in treating tuberculosis. What is most essential is to ensure adherence to the program both from patient’s side and provider side. It is important to take stock of the factors leading to failure of previous programs and to take appropriate measures so that what is implemented now remains the standard of care for TB in years to come.

References

1.      World Health Organization. TB - A Global Emergence. World Health Organization, Geneva, 1994. WHO/TB/ 94.177

2.      World Health Organization, Stop TB Strategy, 2013; Geneva 2013.

3.      World Health Organization, Global Tuberculosis Report 2012; Geneva 2012.

4.      Revised National TB Control Program 2013; tbcindia.nic.in

5.      Fox W, Gordon A, Mitchison D. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946-1986, with relevant publications. Int J Tuberc Lung Dis 1999; 3: S231-S270

6.      WHO Report 2005: WHO/HTM/TB/2005,49. WHO: Geneva; Global tuberculosis control: Surveillance planning financing.

7.      S K Katiyar, S Bihari, S Arun, T Rawat. An Analysis of Failure of Category II DOTS Therapy Indian J Community Med. 2008; 33(2): 129–30.

8.      Directorate General of Health Services. New Delhi: MOHFW GOI; 2009. Central TB Division, TB India 2009 RNTCP status report, in TB India.

9.      Hill AR, Manikal VM, Riska PF. Effectiveness of directly observed therapy (DOT) for tuberculosis: A review of multinational experience reported in 1990-2000. Medicine (Baltimore) 2002; 81:179–93.

10.  Thomas A, Gopi PG, Santha T, Chandrasekaran V, Subramani R, Selvakumar N, et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS program in South India. Int J Tuberc Lung Dis. 2005; 9(5):556–61.

11.  Mehra RK, Dhingra VK, Nish A, Vashist RP. Study of relapse and failure cases of CAT I retreated with CAT II under RNTCP–an eleven year follow up. Indian J Tuberc. 2008; 55:188–91.

12.  Mukherjee A, Sarkar A, Saha I, Biswas B, Bhattacharyya PS. Outcomes of different subgroups of smear-positive retreatment patients under RNTCP in rural West Bengal, India. Rural Remote Health. 2009; 9:926- 31.

13.  G S Azhar. DOTS for TB relapse in India: A systematic review. Lung India. 2012; 29(2): 147–53

14.  Dave P, Rade K, Modi B, SolankiR,Patel P, Shah A, Vadera B. Assessment of Long-term Outcome among New Smear Positive Pulmonary TB Patients Treated with Intermittent Regimen under RNTCP – A Retrospective Cohort Study. Natl J Community Med 2013; 4(2):189-94.

15.  Alvarez TA et al. Prevalence of drug-resistant Mycobacterium tuberculosis in patients under intermittent or daily treatment. J Bras Pneumol. 2009; 35(6):555-60.

16.  Wells AW et al. Implications of the current tuberculosis treatment landscape for future regimen change. Int J Tuberc Lung Dis. 2011; 15(6):746–53.

17.  Volmink J, Garner P - Directly observed therapy for treating tuberculosis (Review) - The Cochrane Library - 2009, Issue 1, http://www.thecochranelibrary.com

18.  Munro SA, Lewin SA, Smith H, Engel ME, Fretheim A, et al. Patient adherence to Tuberculosis treatment: A systematic review of qualitative research. PLoS Med 2007; 4(7): e238.

19.  Satyanarayana S, Nair SA, Chadha SS, Shivashankar R, Sharma G, et al. () From Where Are Tuberculosis Patients Accessing Treatment in India? Results from a Cross-Sectional Community Based Survey of 30 Districts.PLoS ONE 2011; 6(9): e24160.

20.  Anurag Bhargava et al., Mismanagement of Tuberculosis in India: Causes, Consequences, and the Way forward. Hypothesis 2011, 9(1): e7.

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.

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