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

1.  Prasad R, Kumar R. Allergy situation in India: What is being done? Indian J Chest Dis Allied Sci 2013;55:7-8
2.    Chandrika D. Allergic rhinitis in India: An overview. Int J Otorhinolaryngol Head Neck Surg. 2017;3:1-6
3.  Gaur SN, Gupta K, Rajpal S, Singh AB, Rohatigi A. Prevalence of bronchial asthma and allergic rhinitis among urban and rural adult population of Delhi. Indian J Allergy Asthma Immunol 2006; 20: 90 – 97
4. Sole D, Camelo-Nunes IC, Wandalsen GF, Rosario NA, Sarinho EC, Brazilian ISAAC Group. Is allergic rhinitis a trivial disease? Clinics 2011;66:1573-1577
5. Mir E, Panjabi C, Shah A. Impact of allergic rhinitis in school going children. Asia Pac Allergy 2012;2:93-100
6. Sausen VO, Marks KE, Sausen KP, Selg TH. Management of allergic rhinitis. J Pediatr Pharmacol Ther 2005;10:159-73
7.  Van Cauwenberge P, Van Hoecke H. Management of allergic rhinitis. B-ENT, 2005, 1, Suppl. 1, 45-64.      
8. Peh, H. Y., Ho, W. E., Cheng, C., Chan, T. K., Seow, A. C. G., Lim, A. Y., et al. Vitamin E isoform γ-tocotrienol downregulates house dust mite–induced asthma. J Immunol. 2015, 195, 437–44.
9.    Wang, Y., Moreland, M., Wagner, J. G., Ames, B. N., Illek, B., Peden, D. B., et al. Vitamin E forms inhibit IL-13/STAT6-induced eotaxin-3 secretion by up-regulation of PAR4, an endogenous inhibitor of atypical PKC in human lung epithelial cells. J Nutr Biochem. 2012, 23, 602–608.
10.  Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(suppl):S147-34.
11. ARIA At-a-glance pocket reference 2007
12. Kaplan AG, Balter MS, Bell AD, Kim H, Mclvor A. Diagnosis of asthma in adults CMAJ 2009; 181: E210-E220. DOI:10.1503/cmaj.080006
13. Wagner JG, Jiang Q, Harkema JR, Ames BN, Illek B, Roubey RA, et al. Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma. Clin Exp Allergy 2008;38:501-11
14.  Agarwal R, Dhooria S, Aggarwal AN, Maturu VN, Sehgal IS, Muthu V, et al. Guidelines for diagnosis and management of bronchial asthma: Joint ICS/NCCP (I) recommendations. Lung India 2015;32:3-42
15.  Shahar E, Hassoun G, Pollack S. Effect of vitamin E supplementation on the regular treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2004;92:654-58
16. Elenius V, Palomares O, Waris M, Turunen R, Puhakka T, Ruckert B, et al. The relationship of serum vitamins A, D, E and LL-37 levels with allergic status, tonsillar virus detection and immune response. PLoS One 2017;12: e0172350. doi: 10.1371/journal.pone.0172350
17. Cook-Mills JM, Avila PC. Vitamin E and D regulation of allergic asthma immunopathogenesis. Int Immunopharmacol. 2014; 23: 364–72
18. Cook-Mills JM,Abdala-Valencia H, Hartert T. Two faces of vitamin E in the lung. Am J Respir Crit Care Med 2013;188:279-284
19. Cook-Mills J, Gebretsadik T, Abdala-Valencia H, Green J, Larkin EK, Dupont WD. Interaction of vitamin E isoforms on asthma and allergic airway disease. Thorax. 2016; 71: 954–56
20. Allan KM, Prabhu N, Craig LC, McNeil G, Kirby B, McLay J, et al. Maternal vitamin D and E intakes during pregnancy are associated with asthma in children. Eur Respir J 2015;45:1027-36
21. Ghaffari J, Hossaini RF, Khalilian A, Nahanmoghadam N, Salehifar E, Rafatpanah H. Vitamin E supplementation, lung functions and clinical manifestations in children with moderate asthma: A randomized double blind placebo- controlled trial. Iran J Allergy Asthma Immunoll 2014; 13:98-103. 

COPD FACTS

 CHRONIC OBSTRUCTIVE PULMONARY DISEASE: 10 QUESTIONS A GP MUST KNOW

1. What do you mean by Chronic Obstructive Pulmonary Disease (COPD) and what are its types?

COPD is a disease prevalent among middle aged and elderly individuals causing considerable morbidity. This disorder is characterized by progressive air flow limitation that is not fully curable and is associated with an abnormal inflammatory response of the lungs to noxious particles and gases. COPD is both preventable and treatable with some significant extra pulmonary effects contributing to severity in individual patients. Because of the concurrent extra pulmonary effects, COPD is considered as a systemic disease. COPD includes chronic bronchitis and emphysema of which chronic bronchitis is defined clinically whereas emphysema is defined pathologically. Chronic bronchitis is defined as the presence of a chronic productive cough on most of the days for three months, in each of two consecutive years, in a patient in whom other causes of chronic cough have been excluded.  Emphysema is defined as abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.

2. How does COPD evolve in a patient and what are its risk factors?

Inhalation of cigarette smoke or smoke from biomass fuels causes lung inflammation which in turn induces parenchymal destruction and disruption of normal repair process. Pathological changes in COPD include chronic inflammation with increased number of specific inflammatory cell lines and structural changes secondary to repeated injury and repair. Systemic inflammation may accompany these changes and could play an important role in the causation of multiple comorbid conditions. Airflow limitation is caused by a mixture of small airway diseases and parenchymal destruction. Inflammation and narrowing of peripheral airways leads to decreased FEV₁. These pathological change leads to gas trapping and progressive airflow limitation.

Environmental factor becomes the greatest risk for development of COPD. Genetic factors to an extent play a role in the pathogenesis of COPD. Hence it can be concluded that this disease usually arises as a result of gene-environment interaction. The male sex and increasing age are particularly at risk. Cigarette smoking and air pollution resulting from burning of wood and biomass fuels are the major known risk factors for COPD. However there are other factors such as nutrition, infection and occupational exposure which also play a role in its causation.

Cigarette smoking is by far the most commonly encountered risk factor for COPD. Cigarette smokers have a high annual rate of decline of FEV₁ at a rate of 50 ml which is nearly double the value of 30 ml annually present in nonsmokers. In nonsmokers the FEV₁ begins to decline at 30-35 years of age and this may occur earlier in smokers. The risk for COPD in smokers is dose-related. Age at starting to smoke, total pack-years smoked, and current smoking status are predictive of COPD mortality. It is observed that not all smokers develop clinically significant COPD, which suggests that genetic factors may modify the risk.

Other risk factors include passive smoking, exposure to biomass fuel, occupational pollutants, infections and genetic factors. About 80% of the COPD is attributed to smoking, and 15% is due to work-related conditions. Even though a lesser percentage has genetic factors causing COPD, it is mostly due to interplay between environmental and genetic factors.

3. What signs/symptoms can a patient with COPD present to a doctor?

Chronic and progressive dyspnea is the most characteristic symptom of COPD. Cough with sputum production is seen in 30% of patients only. These symptoms may vary day to day and progress over a period of many years. Significant airflow limitation may also be present without chronic dyspnea and/or cough and sputum. Patients may seek medical attention either because of chronic, progressive symptoms or due to acute worsening in exacerbations. Audible wheeze is a predominant symptom associated with bronchial obstruction. This may also vary according to the type and severity of involvement. Absence of wheeze does not rule out COPD as this may not be evident in emphysema.

Fatigue, weight loss and anorexia are associated with long standing COPD. Cachexia is a frequent finding in COPD and is associated with poor functional capacity and increased mortality. It has been observed that 10 to 15 per cent of patients with mild to moderate COPD have significant weight loss whereas the weight loss is observed in 50 per cent of patients with severe COPD.

Chronic bronchitis patients are blotted and cyanotic (Blue bloater) whereas emphysema patients are lean and polycythaemic (Pink puffer). There will be features of hyperinflation in the form of barrel chest, low flat diaphragm and hyper-resonant percussion notes. Auscultation may demonstrate diffuse expiratory polyphonic wheezes. Physical signs of pulmonary hypertension and right heart enlargement/ failure can be elicited in appropriate circumstances.

In some patient a clear distinction between chronic asthma and COPD is not possible. In such patients it is assumed that asthma and COPD coexist (Asthma- COPD overlap). This accounts for approximately 15–25% of the obstructive airway diseases and patients experience worse outcomes compared to asthma or COPD alone.

4. How should a physician approach to a patient with symptoms suggestive of COPD that arrives at his/her clinic for the first time?

COPD is suspected in any patient who has chronic cough with sputum production for at least 3 months in 2 consecutive years or progressive dyspnoea with or without exposure to risk factors. Making a diagnosis relies on clinical judgment based on a combination of history, physical examination and confirmation of the presence of airflow obstruction using spirometry. In clinical practice the progressive and disabling nature of the illness is often overlooked and hence ignoring COPD as simple bronchitis or asthma.

Consider a diagnosis of COPD if any of the following indicators are present.

1)      Persistent Progressive dyspnea that is worsened by exercise.

2)   Chronic cough (intermittent and unproductive also included)

3)   Chronic sputum production

4)   History of exposure to risk factors like tobacco smoke, smoke from household cooking and heating fuels, occupational dusts and chemicals.

5)   Family history of COPD

The initial investigation of choice in an obstructive airway disease is spirometry. If post bronchodilator FEV₁/FVC is <0.70, it confirms the presence of persistent airflow limitation and suggest a diagnosis of COPD.

Criteria for assessing the severity of airflow obstruction (based on the percentage predicted post bronchodilator FEV₁) are as follows:

• Stage I (mild): FEV₁ 80% or greater of predicted
• Stage II (moderate): FEV₁ 50-79% of predicted
• Stage III (severe): FEV1 30-49% of predicted
• Stage IV (very severe): FEV₁ less than 30% of predicted or FEV₁ less than 50% and chronic respiratory failure.

 Chest X-Ray is an important tool even though not specific; X- ray can give you many clues such as

1)         Hyperinflation- Low flat diaphragm, widened rib spaces, tubular heart, hyper-translucency, increased bronchovascular markings and increased retrosternal airspace in lateral view.

2)         Presence of air containing spaces or bullae.

3)         Enlarged proximal pulmonary vessels

CT Thorax is seldom employed as a first level investigation, but is useful to identify and locate bullous changes in the lung.

Arterial blood gas estimation may be needed in acute exacerbation which will show hypoxemia and/ or hypercarbia.

     

5. What investigations should a GP order for a patient of COPD and how could he/she reach a definitive diagnosis?

A detailed history may point to a diagnosis in majority of cases. The nearest differential diagnosis is asthma which can be identified by the episodic nature of breathlessness. Pulse oximetry can pick up hypoxia and peak expiratory flow measurement will give an idea about airfow obstruction. X-Ray chest if available will give certain clues as mentioned earlier regarding hyperinflation which is a feature of COPD. If presented in exacerbation, elevated total WBC count may suggest acute infection as a cause for exacerbation.

6. How should one design a therapy for a COPD patient? What medications can a GP prescribe to such a patient at his/her level?

Physician treating a COPD patient should understand that it is not a curable disease and should not offer cure or attempt overenthusiastic treatment with a curative intent. Patients of COPD should understand the nature of disease, risk factors for its progression and the role that their health care workers must play in order to achieve optimal management and outcomes. Pharmacologic and non -pharmacologic therapies should be guided by disease severity and aim to control symptoms, decrease exacerbations, and improve patient’s functional quality of life.  Aims of treatment

• Control of symptoms.
• Enable the patients for daily activities
• Improve quality of life
• Improve exercise tolerance
• Prevent disease progression
• Prevent and treat exacerbations
• Prevent complications
• Reduce mortality

To guide management COPD is categorized based on symptoms and risk of exacerbations.

• A= Less symptoms, Low risk
• B= More symptoms, low risk
• C= Less symptoms, high risk
• D= More symptoms, High risk.

General practitioners can treat COPD patients with bronchodilators. In group A treat with inhaled form of either short acting beta agonists or short acting anti cholinergics. Oral Theophylline can be used as add on. In group B inhaled long acting beta agonists or anti cholinergics may be used. If response is suboptimal these two drugs can be combined. Theophilline may also be added and short acting beta agonist can be used to control acute symptoms. In group C and D inhaled corticosteroid may be added to LABA and LAMA. Alternate drugs such as Roflumilast may be added if response is not satisfactory. In group D long term oxygen therapy may be initiated and any possibility of surgical treatment may be considered. All patients need pulmonary rehabilitation to improve exercise tolerance. Rarely surgery is of help in selected patients such as those who have large bullous emphysema or those having heterogeneous involvement with severe hyperinflation.

7.  How does acute exacerbations of COPD present? What is meant by decompensated COPD?

COPD exacerbations are important because they are associated with significant morbidity, health care cost and mortality. Acute exacerbation is caused by several factors of which most important are bacterial or viral respiratory tract infections. Air pollution is another contributing factor in a minority of cases. The cause of exacerbations cannot be identified in one-third of cases. Patients with two or more exacerbations per year are classified as frequent exacerbators.

COPD exacerbation is defined as an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond the normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in patients with underlying COPD.

Cardinal symptoms of exacerbation are

1. Increased Sputum volume

2. Sputum purulence

3. Increased dyspnoea

Anthonisen et al graded these exacerbations into 3 types.

·         Type I- all 3 cardinal symptoms are present

·         Type II- 2 cardinal symptoms are present

·         Type 3 one cardinal symptom + one of the followings

1. An upper respiratory infection within the past 5 days.

2. Fever without other cause.

3. Increased wheezing or cough or an increase in heart rate or respiratory rate by 20% compared with baseline.

Sudden worsening of COPD with respiratory failure or cardiac failure denotes decompensation. This usually accompanies acute exacerbations. These patients are identified by the presence of dyspnea, tachypnea, cyanosis and edema.

Causes of an acute decompensation of a COPD Patient are

• Superimposed infection
• Continued smoking
• Non-compliance
• Lack of usual medications or oxygen therapy
• Spontaneous pneumothorax

8. What could be the long term complications of the different forms of COPD?

Chronic obstructive pulmonary disease (COPD) being a chronic, progressive disease, there are many local and systemic complications contributing to its morbidity and mortality. Control of progression and early prevention are the optimal strategies to avoid such complications.

Complications include

● Pneumonia

● Pulmonary Hypertension and Cor pulmonale

● Pneumothorax

● Giant Bullae

● Cardiovascular Disease

● Lung cancer

● Sleep Disorders

● Osteoporosis

● Diabetes

● Psychiatric complications –Depression and / or Anxiety

9. When should a GP seek specialist referral in the management of COPD?

Referral to specialist generally has the purpose to confirm diagnosis, perform additional investigations, optimize and initiate treatment or exclude other illnesses.

Indications are

• Disease onset age <40 years
• Frequent exacerbation despite adequate management
• Rapidly progressive course of disease
• Severe COPD
• Need for oxygen therapy
• Onset of comorbid illness
• Possible indication for surgery

10. What should patients of COPD be advised as regards prevention and rehabilitation of their illness? Can moderate exercise help such patients?

Prevention of COPD is crucial as it is not a curable condition. Prevention usually focuses on smoking cessation. Primary prevention of COPD requires the reduction or avoidance of personal exposure to common risk factors. Avoidance of direct and indirect exposure to tobacco smoke is of primary importance for healthier lungs. Other shared risk factors that should be addressed include low birth weight, poor nutrition, acute respiratory infections of early childhood, indoor and outdoor air pollution and occupational risk factors. Secondary and tertiary prevention involves avoidance of allergens and non-specific triggers, optimal pharmacological treatment, including the use of anti-inflammatory medication. Influenza vaccination reduces lower respiratory tract infections and death in patients with COPD. Pneumococcal polysaccharide vaccine is useful in COPD patients 65 years and older and in younger patients with significant comorbid conditions such as cardiac disease.

Pulmonary rehabilitation includes lower and upper extremity exercise conditioning, breathing retraining, education, and psychosocial support. Smoking cessation, oxygen therapy, bronchodilators, antibiotic use, nutritional support, and respiratory muscle training are also being included in many rehabilitation programs. The primary components of a comprehensive program are:

·         Patient assessment.

·         Patient exercise training.

·         Patient education.

·         Program evaluation.

·         Maintenance.

Patients with chronic obstructive pulmonary disease (COPD) often try to reduce their physical activity because of the fear of worsening dyspnea. This lead to progressive deconditioning due to inactivity, and gradually patient become dyspnoeic even at minimum physical demands. Pulmonary rehabilitation aims to break this cycle. Benefits of pulmonary rehabilitation include decreased dyspnea, improved health-related quality of life, fewer days of hospitalization, and decreased health-care cost. Initiation of a rehabilitation schedule during or immediately after hospital admission for acute on chronic respiratory failure reduces the extent of functional decline and leads to early recovery.