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“Cold morning today, doctor”, a 60-year old patient manages to so say before sitting down with effort, clutching a crumbled packet of Lucky Strikes in his left hand, complaining that he’s been coughing for nearly three months now, for two years, and that this “sputum never stops”. He continues to mumble something to the effect that his breathing requires effort and that he feels out of breath and can’t “get enough air in”. The patient has a pink complexion, his respiratory rate is a little high and he has pursed lips. Perhaps the diagnosis is smoker’s lung or “pink puffer”. However, he then explains that sometimes his lips are blue and that his ankles swell a bit. Could the diagnosis be “blue bloater”? However, this terminology is no longer accepted as useful as most patients with chronic obstructive pulmonary disease (COPD) have a combination of both emphysema and chronic bronchitis.1,2

One of the earliest descriptions of probable emphysema was made in 1679 by Bonet of a condition of "voluminous lungs".In 1769, Morgagni (Figure 1) described lungs which were"turgid, particularly from air". 4,5 1721, the first drawings of this condition were made by Ruysh. 5These were followed with pictures by Baillie in 1789, and descriptions of the destructive nature of the condition.In 1814, Badham used "catarrh" to describe the coughing and excess mucus in chronic bronchitis.Laënnec, the physician who invented the stethoscope, used the term "emphysema" in his book, A treatise on the diseases of the chest and of mediate auscultation, (1837) to describe lungs which did not collapse when he opened the chest during an autopsy.Laënnec wrote on emphysema: "The disease which I designate by this title is very little known, and has not hitherto been correctly described by any author.I, for a long time, thought it very uncommon, because I had observed only a few cases of it.But since I have made use of the stethoscope, I have verified its existence as well on the living, as on the dead subject, and am led to consider it as by no means infrequent.I consider many cases of asthma, usually deemed nervous, as depending on this cause.The chief reason of this affection having been so completely overlooked is that it is in some sort merely the exaggeration of the natural condition of the viscus".
Smoking was rare in this era, but it is a fact that emphysema may occur in non-smokers, particularly with a familial predisposition, or from environmental-provoking factors.Laënnec continued: "In opening the chest, it is not unusual to find that the lungs do not collapse, but they fill up the cavity completely on each side of the heart.When experienced, this will appear full of air.The bronchus of the trachea are often at the same time a good deal filled with mucous fluid".Thus, Laënnec had described a combination of emphysema and chronic bronchitis! 4 The term "chronic bronchitis" came into use in 1808, while the term COPD was first believed to have been used in 1965. 1,4Previously, it was known by a number of different names, including chronic obstructive bronchopulmonary disease, chronic obstructive respiratory disease, chronic air flow obstruction, chronic air flow limitation, chronic obstructive lung disease, non-specific chronic pulmonary disease and diffuse obstructive pulmonary syndrome.The terms "chronic bronchitis" and "emphysema" were formally defined in 1959 at the CIBA guest symposium, and in 1962 at the American Thoracic Society Committee meeting on diagnostic standards. 6

Definition
COPD is defined as follows by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a project initiated by the National Heart, Lung and Blood Institute (NHLBI) and the World Health Organization (WHO): 7 "COPD, a common preventable and treatable disease, is characterised by air flow limitation that is usually progressive, and associated with an enhanced chronic inflammatory response in the airways and the lungs to noxious particles or gases.Exacerbations and co-morbidities contribute to the overall severity in individual patients"."Chronic bronchitis" is defined as a chronic productive cough for three months in each of two successive years in a patient in whom other causes of chronic coughing, e.g.bronchiectasis, have been excluded. 8It may precede or follow the development of air flow limitation. 9,10This definition has been used in many studies, despite the arbitrarily selected symptom duration."Emphysema" is defined by the abnormal and permanent enlargement of the air spaces distal to the terminal bronchioles, which is accompanied by destruction of the air space walls, without obvious fibrosis. 11The exclusion of obvious fibrosis was intended to distinguish the COPD disease, i.e. definition, clinical manifestations, diagnosis and staging alveolar destruction due to emphysema, from that due to interstitial pneumonia.However, increased collagen in the lungs of patients with mild COPD has been found in many studies, indicating that fibrosis can be a component of emphysema. 12,13ile emphysema can exist in individuals who do not have air flow obstruction, it is more common in patients with moderate or severe air flow obstruction. 7,14

Population and epidemiology
Worldwide, COPD affects roughly 329 million people, or nearly 5% of the population. 15In 2013, it resulted in 2.9 million deaths, up from 2.4 million deaths in 1990. 7The number of deaths is projected to increase owing to higher smoking rates and an ageing population in many countries. 8obally, roughly 10% of people aged ≥ 40 years have air flow limitation, i.e.GOLD stage 2 or worse [forced expiratory volume in one second (FEV 1 ) ≤ 80% predicted], and up to 25% may have GOLD stage 1 (FEV 1 ≥ 80% predicted, but FEV 1 /forced vital capacity ≤ 0.7).It is also suspected that up to 60-85% of people with COPD with mostly mild or moderate severity are undiagnosed. 16e disease affects men and women almost equally, as there has been increased tobacco use in women in the developed world.The global numbers are expected to continue to increase as risk factors remain common and the population continues to get older. 17PD is considered to be the fourth leading cause of death worldwide.Mortality associated with COPD is rising, while that linked to cardiovascular disease is falling.COPD is expected to be the third leading cause of death in the next 15-20 years. 16

Causes
Tobacco smoke is the primary cause of COPD, with occupational exposure and pollution from indoor fires being a significant contributing factor. 18A number of industries and sources have been implicated, including high levels of dust in coal mining, gold mining and the cotton textile industry, occupations which involve cadmium and isocyanates, and fumes from welding. 19he page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd21 Working in agriculture is also a risk. 20Typically, this exposure occurs over several decades before symptoms develop. 18person's genetic make-up also affects the risk. 18It is more common in relatives of those with COPD who smoke than in unrelated smokers. 3Currently, the only clearly inherited risk factor is alpha-1 antitrypsin (AAT) deficiency.This risk is particularly high if someone deficient in AAT also smokes.AAT inhibits a wide variety of proteases.It protects tissue from the enzymes of inflammatory cells, especially neutrophil elastase.In its absence, i.e. in ATT deficiency, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema or COPD in adults, and cirrhosis in adults or children. 21 is responsible for roughly 1-5% of cases, and the condition is present in 3-4 in 10 000 people. 21,22Other genetic factors are being investigated, of which there are likely to be many. 20

Acute exacerbations
Acute exacerbations of COPD, also known as acute exacerbations of chronic bronchitis, signify a sudden worsening of the COPD symptoms, i.e. shortness of breath, and the quantity and colour of the phlegm, which typically lasts for several days.It may be triggered by an infection with bacteria or viruses, or by environmental pollutants.At times, the cause or reason is simply not known.Improper use of medication can also lead to this. 23fections appear to be the cause in 50-75% of cases, 23,24 with bacteria in 25% (including Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis), viruses in 25% (rhinovirus, coronavirus and parainfluenza), and both in 25%.Cold temperature may also play a role.Exacerbations occur more commonly in winter. 25ose with more severe underlying disease have more frequent exacerbations of 1.8 per year with mild disease, 2-3 per year with moderate disease, and 3.4 per year with severe disease.Those with many exacerbations have a faster rate of deterioration of their lung function. 26Congestive heart failure and pulmonary emboli can worsen symptoms in those with pre-existing COPD. 27

Pathophysiology
COPD is an obstructive lung disease in which chronic incompletely reversible poor air flow (air flow limitation) and the inability to breathe out fully (air trapping) exist. 27This develops as a significant and chronic inflammatory response to inhaled irritants. 1Chronic bacterial infections may also add to this inflammatory state. 26The inflammatory cells involved include neutrophil granulocytes and macrophages.Those who smoke additionally have cytotoxic T lymphocyte involvement, and some patients with COPD have eosinophil involvement, similar to that in asthma.
COPD is characterised by both the destruction of lung parenchyma with loss of elastic recoil (causing emphysema), and infiltration of the walls of the small airways by inflammatory cells (causing chronic bronchiolitis or bronchitis.These two broad phenotypes are distinct entities, and they coexist and overlap in varying degrees in virtually everyone with COPD.The reasons for these variable phenotypes and their clinical importance are not that well understood.Chronic poorly controlled COPD can lead to hypoxia, which occurs from poor gas exchange due to decreased ventilation from airway obstruction, hyperinflation and a reduced desire to breathe. 3 Airway inflammation is also increased during exacerbations, resulting in increased hyperinflation, reduced expiratory air flow and worsening of the gas transfer.This can also lead to insufficient ventilation, and eventually hypoxia.If present for a prolonged period, it can result in narrowing of the pulmonary arteries, while emphysema leads to the breakdown of capillaries in the lungs.Both these changes result in increased blood pressure in the pulmonary arteries, placing the patient at increased risk of developing cor pulmonale. 3

Management
There is no known cure for COPD, but the symptoms are treatable, and its progression can be delayed.The major goals of management are to reduce the risk factors, manage stable COPD, prevent and treat acute exacerbations and manage associated illnesses. 28her recommendations include an influenza vaccination once a year, a pneumococcal vaccination once every five years, and reduction in exposure to environmental air pollution. 27Palliative care may reduce the symptoms in those with advanced disease.Supplemental oxygen has been shown to slow the progress of this disease.It has now been shown that giving morphine improves the feelings or sensations of shortness of breath.Noninvasive ventilation may be used to support breathing. 29

Nonpharmacological
First and foremost, it is important to quit smoking.Keeping people from starting to smoke is a key aspect of preventing COPD.Stopping smoking in those who smoke is the only measure that has been shown to slow the progression of COPD. 30Even at a late stage of the disease, it can reduce the rate of worsening lung function and delay the onset of disability and death.Stopping smoking decreases the risk of death by nearly 18%. 27

Exercise
A programme with the aim of pulmonary rehabilitation should include coordinated aspects of exercise, disease management and counselling. 19Pulmonary rehabilitation appears to improve overall quality of life and the ability to exercise, and reduce mortality in those who have experienced a recent exacerbation. 31owever, breathing exercises by themselves appear to play a limited role. 18Some authors have shown that pursed lip breathing exercises may be useful. 16

Lung volume reduction surgery
Consideration of lung volume reduction surgery is recommended in all patients with very severe COPD.The surgery provides a mortality reduction and improvement in quality of life, especially in patients with upper lobe-predominant disease and poor exercise capacity or ability. 32

Non-surgical, bronchoscopic lung volume reduction
Because of the morbidity and risk associated with lung volume reduction surgery, and its subsequent unpopularity, numerous companies and investigators have sought to produce a medical device that could be placed bronchoscopically, and which would reduce dead space ventilation, i.e. lung volume reduction surgery without the surgery.To date, none of these devices have worked effectively enough for their use to be recommended outside clinical trials.The most recent example was bronchoscopic lung volume reduction in the Exhale Airway Stents for Emphysema (EASE) trial, in which it was demonstrated that bronchoscopically placed airway stents with a one-way valve did not improve airway mechanics or dyspnoea.
Perhaps collateral ventilation or interalveolar air drift through the pores of Kohn are the most likely answers to this failure or ineffectiveness.These are miniscule anatomical intercommunications which allow air to fill back into emphysematous areas after air has been removed through the implanted device. 32

Pharmacological
The GOLD guideline treatment table is the most well-known and accepted guideline for the treatment of COPD.It is summarised in Table 1. 16

Bronchodilators
Inhaled bronchodilators are the primary medication used, and result in a small overall benefit. 4,33There are two major types, β 2 agonists and anticholinergics.Both exist in long-and shortacting forms.They reduce shortness of breath, wheezing and exercise limitation, resulting in improved quality of life. 34It is unclear whether or not they change the progression of the underlying disease. 27ng-acting bronchodilators (formoterol and salmeterol), and long-acting anticholinergics (tiotropium), have similar efficacy, including: • An improvement in post-bronchodilator FEV 1 , i.e. ~50-100 ml.
• An improvement in dyspnoea, i.e. ~3 points using the St George's respiratory questionnaire.
• A reduction in daily, short-acting beta agonist use by ~1 inhalation.
• The prevention of COPD exacerbations was better with tiotropium than salmeterol in one randomised trial, but the effect was quite small. 35ng-acting beta agonists (LABAs) have a cardiac effect, but have not been found to cause cardiovascular events, and don't have the very slightly increased risk of death associated with LABA monotherapy for asthma.
Tiotropium has been suspected of causing cardiovascular events based on observational trials, but the current consensus [based mainly on Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) randomised trial data and a meta-analysis] is that it does not cause cardiovascular events. 36

Methylxanthines
The use of theophylline was summarised in a review carried out by Vaz Fragoso as follows.Theophylline may favourably affect the major factors associated with functional impairment in COPD, such as dyspnoea, exercise capacity, respiratory mechanics and respiratory muscle strength.Theophylline is generally considered to be a third-line bronchodilator drug in chronic COPD, after inhaled anticholinergics and beta 2 agonists.
Despite both smoking cessation and the use of inhaled bronchodilators, theophylline may reduce functional impairment and exacerbation frequency in patients with persistent functional impairment, but the effect in individual patients is variable.In general, patients with COPD can be adequately treated with serum levels in the 8-12 µg/ml range.Once an appropriate serum level has been achieved, subsequent measurements can be made at 6-to 12-month intervals, or if the patient's clinical status or concomitant medications change.When compared to acute intoxication, chronic theophylline overmedication is associated with a greater frequency of major toxicity, occurs at The page number in the footer is not for bibliographic referencing www.tandfonline.com/oemd23 relatively lower theophylline levels, and cannot be predicted by the peak serum theophylline concentration.
Methylxanthines are not recommended for routine management in acute COPD exacerbations.In addition to a lack of efficacy in this setting, methylxanthines increase the likelihood of sideeffects, e.g.nausea, vomiting and arrythmias. 37

Corticosteroids
Corticosteroids are usually used in inhaled form, but may also be used orally to treat and prevent acute exacerbations.While inhaled corticosteroids have not shown benefit in people with mild COPD, they decrease acute exacerbations in those with either moderate or severe disease. 38terestingly, in the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial, it was demonstrated that a longer course of oral prednisone did not reduce the rate of repeat COPD exacerbations.Fifty-seven patients taking prednisone for 14 days had a repeat COPD exacerbation (37%), compared to 56 taking prednisone for 5 days (36%).Extra prednisone did not prolong the time to the next COPD exacerbation. 39An important consequence of this was reduced corticosteroid exposure, and thus the side-effects.
When used in combination with a LABA, they decreased mortality more than either an inhaled corticosteroid or a LABA alone. 40ey have no effect by themselves on overall one-year mortality, and are associated with an increased rate of pneumonia. 41 is unclear whether or not they affect the progression of the disease. 4Long-term treatment with an oral glucocorticoidsteroid is associated with significant side-effects. 41haled corticosteroid and LABA combination products cause pneumonia in a tiny proportion of patients.However, combination products may also reduce mortality slightly, based on the just barely negative Towards a Revolution in COPD Health (TORCH) trial.Inhaled corticosteroid/LABA combination products do not seem to cause increased risk of death from pneumonia.
Even when inhaled, corticosteroids probably cause osteoporosis in a small number of susceptible patients.
The evidence is inconclusive as to whether any drug treatments for COPD modify (slow) the disease course or reduce mortality, but data from several clinical trials suggests that both inhaled corticosteroid/LABA combination products and tiotropium may lessen a decline in FEV 1 and slightly reduce mortality risk.
In fact, better outcomes from "triple therapy", i.e. an inhaled corticosteroid, a long-acting beta-agonist and tiotropium given together, were suggested in an observational study on symptomatic patients with severe to very severe stable COPD. 42

Treatment
Guidelines are available for the treatment of COPD exacerbations.

They mainly recommend:
• Increasing the dose of short-acting bronchodilators, i.e. albuterol and/or ipratropium.
• Oxygen and ventilatory support for respiratory failure.A recent review showed that noninvasive positive pressure ventilation was likely to improve outcomes from COPD exacerbations.
• Considering theophylline for severe exacerbations.
• Adding oral corticosteroids, if bronchodilators are not successful.
• Treating most COPD exacerbations with 40 mg prednisone for five days, i.e. the 2014 GOLD guidelines.This was a significant change from the previous recommendation of 10-14 days.As discussed previously, five days of steroids was suggested as adequate treatment for COPD exacerbations in most patients in the REDUCE study. 43Antibiotics are indicated in a patient with increased sputum production, purulent sputum, increased dyspnoea and an elevated white count, or who is febrile. 44e choice of antibiotics is also dependent upon the severity of pneumoniae may have to be added. 45

Replacing enzymes
AAT-deficient individuals who have, or show signs of developing, significant emphysema, can be augmented with a pooled, purified, human plasma protein concentrate replacement for the missing enzyme.Practitioners should immunise patients against hepatitis regardless.
Weekly intravenous infusions of AAT protein concentrates restore serum and alveolar AAT concentrations to protective levels.
It has not been proved in any controlled studies that intravenous augmentation therapy improves survival or slows the rate of emphysema progression.Results from the National Institutes of Health (NIH) patient registry and a comparison of Danish and German registries have been published, and both suggest that augmentation therapy has beneficial effects.Although they were not controlled treatment trials, the similarity of the results suggests that the findings are significant.
The NIH report described an overall death rate 1.5 times higher for those who did not receive augmentation therapy and a rate of FEV 1 decline (54 ml/year) in AAT-deficient individuals, roughly twice that of healthy non-smokers, but approximately 50% that of smokers (108 ml/year).Augmentation therapy did not improve the average FEV 1 decline (54 ml/year).However, participants with moderate air flow obstruction (FEV 1 35-60% of the predicted value) experienced a slower rate of decline, i.e. a mean difference of 27 ml/year).
Augmentation therapy is recommended in the current guidelines for individuals with abnormal AAT genotypes, who have AAT levels below 11 μm and documented evidence of air flow obstruction in pulmonary function tests. 46ile firm guidelines have not been developed with respect to initiating or continuing augmentation therapy, most pulmonary physicians require the serum level to be below the threshold protective value, and the patient to have one or more of the following: signs of significant lung disease, such as chronic productive cough or unusual frequency of lower respiratory infection, air flow obstruction, accelerated decline of FEV 1 , or chest radiographic or computed tomography evidence of emphysema. 46,47

Some interesting developments
The role of the new phosphodiesterase-4 inhibitors (not properly discerned yet) has been the focus of relative recent new developments.Cochrane published an analysis on these new agents in 2011.Roflumilast, and its sibling, cilomilast, only improved post-bronchodilator FEV 1 by ~50 ml, and reduced exacerbation frequency by a relative 17%, in selected patients with GOLD stage 3-4 COPD who experienced coughing with sputum changes and had a history of exacerbations.
However, patients reported that these medications only provided a small effect on levels of breathlessness and quality of life.On the other hand, 5-10% of patients on trials who received roflumilast or cilomilast reported side-effects such as diarrhoea, nausea, vomiting and nasal congestion.There was also a twoto threefold increase in the risk of sleep or mood disturbance, although the total number of reported incidents was still small overall.There was no effect on rates of hospitalisation and deaths.Furthermore, because both exhibit anti-inflammatory effects, there were suggestions of an additive benefit on top of the inhaled corticosteroids, but the number of studies reporting this was small. 42st-marketing data are essential to determine the new agents' real-world efficacy and risk of adverse events.Also, they have not yet been included in GOLD or other society treatment guidelines.

The role of long-term use of antibiotics
Macrolide antibiotics are increasingly recognised for their salutary anti-inflammatory effects in lung disease, potentially distinct from any antimicrobial effect.
It was noted by Albert et al. in a randomised trial that of 1 142 patients with severe COPD (FEV 1 ~40% predicted) who were randomised to take either azithromycin 250 mg or placebo daily for one year, those taking azithromycin experienced fewer exacerbations, described as follows: 47 • There was a 27% reduction in exacerbations.
• There was a delay of 92 days in median time to the first exacerbation (174 vs. 266 days).
• According to the St George's respiratory questionnaire, quality of life improved by 2.8 points vs. 0.6 (with 4 being accepted as "clinically significant").However, sadly, at least 32 more people in the azithromycin group experienced hearing loss (142 vs. 110), and hearing did not return to baseline on repeat testing in most.

Conclusion
COPD, whether chronic or acute, is a very distressing debilitating condition.Acute exacerbations can be partially prevented.Some Regular exercise, appropriate rest and healthy nutrition are advocated, as well as avoiding people who are currently infected with a cold or influenza, maintaining good fluid intake, and lastly, humidifying the home, in order to help reduce the formation of thick sputum and chest congestion.

Figure 1 :
Figure 1: Giovanni Battista Morgagni, who provided one of the earliest recorded descriptions of emphysema in 1769 the symptoms."Simple" COPD generally refers to a person aged ≤ 65 years, with fewer than four exacerbations per year, minimal or moderate impairment in respiratory function and no co-morbid disease.Therapy in patients with "simple" COPD should target H. influenzae, M. catarrhalis and S. pneumoniae, and possibly pathogens of atypical pneumonia.The first-line treatment is a beta-lactam antibiotic, such as amoxicillin.The choice depends upon resistance patterns.More complicated bronchitis occurs when the patient is aged ≥ 65 years, has four or more exacerbations per year, a FEV 1 :FVC ratio of less than 50% on spirometry, has failed to respond to previous antibiotic treatment, and/or has co-morbidity.Treatment in these cases should target Gram-negative bacteria.The possibility of high antibiotic resistance should be considered.Sputum culture results are of great value in determining antibiotic resistance.The first-line treatment is cefuroxime or co-amoxiclav.Third-line treatment, as well as treatment in penicillin-allergic patients, is a fluoroquinolone, such as ciprofloxacin.An agent active against S.
infections can be averted by vaccination against pathogens such as influenza and S. pneumoniae.Regular medication use can prevent COPD exacerbations.LABAs, long-acting anticholinergics and inhaled corticosteroids ("triple-therapy") are now emerging as a very useful approach to managing COPD and reducing exacerbations.Important methods of prevention include smoking cessation; avoiding dust, passive smoking and other inhaled irritants; and yearly influenza and five-year pneumococcal vaccinations.Promising avenues for treating AAT deficiency exist.

Table 1 :
The Global Initiative for Chronic Obstructive Lung Disease guideline for the treatment of chronic obstructive pulmonary disease * All patients should receive smoking cessation counselling and an influenza vaccination COPD: chronic obstructive pulmonary disease, FVC: forced vital capacity, FEV 1 : forced expiratory volume in one second