COPD: Current Therapeutic Concepts

DEFINITION
     Chronic obstructive pulmonary disease (COPD) is also referred to in various clinical settings as chronic obstructive airway disease (COAD) as well as chronic obstructive lung disease (COLD).1 Regardless of the preferred acronym, the larger definition often encompasses the various pathologies involved not only in emphysema and chronic bronchitis, but asthma, bronchiectasis, and cystic fibrosis as well.C Various experts, including both the American Thoracic Society and the European Respiratory Society, prefer to limit the definition to include only chronic bronchitis and emphysema, conditions which usually coexist to some degree.1
     Further, COPD is often defined by reduced maximal expiratory flow and slow forced emptying of the lungs that fail to change significantly over a period of several months and are minimally reversible by bronchodilators.1 This last criterion usually excludes asthma from most discussions. In fact, a primary diagnostic goal is differentiation between asthmatic and non-asthmatic COPD,Q with a narrowing of the definition to include only manifestations minimally ameliorated by bronchodilators. Chronic bronchitis and emphysema are by far the most common forms of COPD, and incidence of both has continued to rise along with the prevalence of smoking, increasing by some 33% between 1979 and 1991.D An estimated 15 million Americans suffer from these two disorders, and 90% of sufferers are affected by some degree of chronic bronchitis.
     It is important to recognize, though, that asthma frequently coexists to some degree with other COPDs and that aspects of asthma like hyper-reactivity of the airways and inflammation tend to be shared among the other COPDs to some degree.E,F Mounting evidence confirms the involvement of inflammatory processes in all forms of COPD.3,4,O While first-line therapies for asthma focus on the beta-2 agonists, inhaled corticosteroids, and the “mast-cell stabilizers,” management strategies differ for the other COPDs according to their vastly different pathophysiologies, depending upon the degree to which atopic asthma might be involved and to which chronic bronchitis and emphysema may coexist.

PRESENTATION AND PATHOPHYSIOLOGY
     Chronic bronchitis and emphysema are strongly associated with smoking, so much so that their occurrence in patients who have never smoked is a rarity, accounting for only a small percentage of overall incidence. Not all smokers, though, develop COPD; and not all COPD victims have smoked or even been exposed to sufficient environmental pollution to account for disease development.1 Thus, a genetic predisposition or susceptibility is strongly suspected, and in a small percentage of suffers well documented.
     Elastin, a structural component of many tissues, is largely responsible for maintaining the normal elasticity of those tissues.1 Pulmonary parenchymal tissue that surrounds the alveoli, alveolar ducts, and respiratory bronchioles depends upon its elastin component to return alveoli and associated tissues expanded by inspiration to their normal expired volume, which is essential for proper respiratory function.C Elastin, as with other supportive components like bone or cartilage, is perpetually and necessarily broken down and replaced with new components, a process that depends upon the proper function of the breakdown and synthetic components to maintain an optimal equilibrium. In the case of elastin, breakdown is effected by neutrophil elastase,O that is in turn disabled by its natural protease inhibitor, alpha-1 antitrypsin (AAT).
     Inadequate AAT leads to overabundance of elastase; disrupted equilibrium; net loss of elastin; reduced alveolar and bronchiolar elasticity (elastic recoil);A reduced alveolar surface area, capillary perfusion, and perfusion capacity;K,I and expanded expired volume, typically affecting all elastic tissues beyond the terminal bronchiole.C Such damage has so far been irreversible, and the resulting hyperinflation means that the patient has to work harder to attain adequate air intake to avoid hypoxia. The diaphragm is displaced caudally, creating a situation where it must work harder to accomplish its function;J and placing increased burdens on ancillary breathing muscles to eventually create the typical “barrel-chested” appearance of the patient suffering from chronic hyperinflation. Long-term hypoxia eventually leads to cor pulmonale, right ventricular decompensation from chronic hypoxemia (low oxygen blood levels) and hypercapnea, (elevated carbon dioxide blood levels). This typically includes elevated jugular venous pressure (evident from distention), peripheral edema, hepatic congestion, flapping tremor, and renal dysfunction with fluid and salt retention.
     Hereditary AAT deficiency is an autosomal recessive trait seen primarily in Caucasians of Northern European descent. The heterozygous PiMZ phenotype occurs in about 3% and the homozygous PiZZ phenotype occurs in about 0.1% of the general population, whose majority are of the PiMM phenotype expressing normal levels of AAT. Though PiMZ individuals may have low levels of AAT and a corresponding increased risk of pulmonary disease, PiZZ individuals typically have much lower levels and bear far greater risk. Those PiZZ individuals with extremely low levels of AAT often develop panacinar (affecting the entire lung) emphysema at an early age (average age of 45)O even in the absence of significant environmental risk factors; but the varying degrees of deficiency coupled with smoking or other environmental challenge correlate well with the incidence of COPD in general and emphysema in particular.1
     Overabundance of elastase can also be a function of inflammation, as emphysema, asthma, and chronic bronchitis, particularly in smokers, is associated with markedly increased pulmonary parenchymal infiltration by polymorphonuclear leucocytes (PMNs), neutrophils, and macrophages that elevate local levels of elastase themselves.H,I,J,O Smoking actually reduces the association rate constant for AAT and elastase by a factor of 2000. Local pulmonary inflammation leads to production of hydrogen peroxide and myeloperoxidase by macrophages and activated neutrophils, which oxidize AAT to increase levels of elastase and further perpetuate the inflammation. At the same time, optimal levels of AAT tend to suppress inflammation via inhibition of leukotriene B4, interleukin 1, tumor necrosis factor, and platelet activating factor, all essential inflammatory chemotactic factors that recruit inflammatory cells to local tissues. Thus, not only does smoking increase the risk of developing COPD, inadequate control of the inflammation in asthma does also.O
      Emphysema is characterized by hyperinflation primarily affecting the terminal bronchioles and alveoli. Not only is respiration impeded by impaired alveolar perfusion capabilities, but the hyperinflation creates “dead air” spaces that cannot be adequately ventilated. Thus gas exchange is impeded by both lack of perfusion capability and by lower oxygen content of alveolar air. In smokers, the central and upper lobes of the lung are usually most significantly affected; while AAT deficiency usually involves anterior and lower lobes.C
     Though radiological examination typically reveals obvious hyperinflation, flattened diaphragm, and narrowed heart (heard best only over the xyphosternum), diagnosis is often possible without it. Patients are almost always long-term smokers that breathe rapidly with accessory muscles as they lean forward on their arms, cough unproductively, often tend toward wasting, usually without rhonchi.
     Chronic bronchitis, on the other hand, is characterized by chronic inflammation of airways more toward the trunk of the bronchial tree. The inflammation leads to swelling of affected tissues, causing narrowing of the affected airways; and it leads to hypersecretion of mucus resulting in increased sputum production and eventual hypertrophy mucus cells. Patients may breathe normally in the absence of acute exacerbation, in spite of cyanosis, rhonchi, and edema.C Diagnosis is via clinical definition, with productive cough on most days for 3 months per year in 2 consecutive years.3
     Patients commonly suffer from both disease processes, and the diagnosis can be complicated by asthma as well. Thus, though cough is generally present, it may be productive or non-productive; and the patient may or may not exhibit labored breathing, cyanosis.3 Wheezing is common, and positive response to beta-2 agonists is generally diagnostic for the presence of asthma in the clinical picture. Patients may present initially with acute exacerbations that may involve either viral or bacterial infections ranging from acute bronchitis to pneumonia, which must be assessed and suitably addressed with appropriate antibiotic therapy. Assessment via pulmonary function tests will determine the necessity of either acute or chronic oxygen support.

MAINTENANCE THERAPY
     While lung transplant and volume reduction surgery can provide dramatic improvement for some patients, these surgical procedures are a larger topic. Similarly, management of acute exacerbations can quickly expand into a topic unto itself. Thus, the focus of routine medical management is on educating the patient in efforts to restore or maintain optimum lung function and daily activity, prevent or minimize exacerbations, and to retard progression of the disease.R

Smoking Cessation
     Since most COPD patients are smokers, and since the association of disease manifestation with smoking is so strong, smoking cessation efforts are the single most significant essential measure for long-term prevention of exacerbation and survival. Progression of COPD permanent damage is slowed to approximately that of non-smokers with successful smoking cessation after a period of about 6 months; but deterioration is rapid in those who refuse to quit smoking. Thus smoking cessation should be supported by whatever means necessary, whether by professional counseling efforts, nicotine replacement or bupropion therapy. Though some patients are successful in this effort simply by going “cold turkey,” most smokers relapse from 3 up to 10 times before successful cessation is accomplished; so it is important to follow relapse with renewed determination, not fatalistic resignation.
      Similarly, elimination of exposure to contributory environmental or occupational pollutants/irritants may be an essential component for the treatment plan. The patient can hardly expect to improve his chances of survival if unwilling to make the necessary lifestyle changes to avoid further exacerbation.

Immunization
     Since the COPD patient is at high risk of pulmonary infection and faces severe risks of dire consequences resulting from such infections, every effort should be made to minimize such exacerbations. Yearly immunization against influenza, as well as against S. pneumonia repeated every 6 years, is essential to limit such infections;2,Q though the patient remains at risk for a host of other viral and bacterial infections.

Bronchodilators
      Beta-2 agonists, though the hallmark of asthma rescue, may or may not produce a significant therapeutic contribution for the COPD patient. Since the COPD patient is generally older and in poorer health than the typical purely atopic asthmatic, side effects from the beta-2 agonists, regardless of receptor specificity, tend to pose problems in COPD. Responsiveness to beta-2 stimulation tends to decrease with age and with chronic use, so higher doses may be needed for significant effect even in the asthmatic under those conditions. Since beta-2 agonists may not be optimally effective in COPD, the tendency toward overuse must be recognized along with the consequences thereof. Tachycardia, hypertension, and even cardiovascular events become potential liabilities with inhaled beta-2 agonists in a patient population noted for advanced age, smoking, and comorbid cardiovascular disease. Oral administration of beta-2 agonists is generally reserved only for those patients unable to utilize a metered-dose inhaler (MDI) or nebulizer effectively, for side effects with this systemic administration are an even greater liability.
     Ipratropium bromide, though, with its anticholinergic vagal suppression of bronchial constriction, is recognized as the first-line treatment of choice in non-asthmatic COPD. Administered via inhalation, ipratropium bromide has almost negligible side effects in therapeutic dosages (up to 6 inhalations 4 times daily via metered-dose inhaler) with what is generally considered greater efficacy than with beta-2 agonists. With its longer onset of action of about 15 minutes and longer duration of action of up to 8 hours, it is generally more appropriate for routine dosing than as-needed use. Since COPD entails chronic bronchoconstriction rather than acute attacks, the longer onset of action is seldom a real disadvantage. In addition to its benefits of bronchodilation, it also reduces sputum volume without affecting viscosity,R a factor particularly advantageous in chronic bronchitis. Though caution may be in order for the patient with glaucoma, urinary retention, or dry mouth, systemic side effects from even high nebulized doses of ipratropium are rare.
     While most non-asthmatic COPD responds poorly to beta-2 agonists alone, some measure of relief may be noticed by some patients, and most experience some synergism by adding an inhaled beta-2 agonist to a regimen entailing maximum dosing of ipratropium bromide. This may be due in part to the fact that asthma so often coexists to some degree with emphysema and/or chronic bronchitis; but combining the two agents typically produces greater efficacy and longer duration of action, further reducing the likelihood of beta-2 side effects or complications. Combivent(TM), which combines albuterol with ipratropium bromide in a single MDI can often provide an optimum dose of both and enhance convenience and compliance at the same time, as non-compliance with multiple MDIs is a significant problem in this patient population.
     Methylxanthines, having been long used in COPD, provide a number of well-documented advantages in long-term management. Though theophylline provides no more bronchodilation than the beta-2 agonists, long-acting dosage forms can provide an added measure of overnight relief, an advantage that is being reevaluated in light of the availability of metered-dose salmeterol. Theophylline has other advantages, though, that cannot be overlooked. Efficacy does not depend upon proper use of an MDI; and its documented enhancement of collateral ventilation, repiratory muscle strength and endurance, right pulmonary function, mucociliary clearance, and central respiratory drive cannot be overlooked. It has even been demonstrated to contribute to the reduction of inflammation of the airways.2
      Theophylline’s relatively narrow therapeutic index lends itself to frequent and significant side effects (nausea, tachycardia, dyspepsia, and tremor), especially at blood levels that exceed 15mg/l. With a therapeutic range between 10 and 20mg/l and extensive metabolism via the cytochrome P450 enzyme system, levels are readily and unpredictably reduced by enzyme inducers (including smoking) and raised by CYP1A2 and 3A4 inhibitors to lower therapeutic efficacy or cause side effects. (See Table 1) Thus, theophylline should generally be reserved for the COPD patient who fails to respond or fail to comply with MDI bronchodilator administration.2

Table 1.
Some Significant Drug Interactions With Theophylline

Blood levels are increased by these enzyme inhibitors:
Macrolide antibiotics: Clarithromycin, erythromycin, and troleandomycin, though azithromycin might be considered instead.
Fluoroquinolone antibiotics: Ciprofloxacin and enoxacin. Ofloxacin and lomefloxacin may be considered instead, as they have little effect on theophylline levels. Cimetidine: Consider ranitidine, nizatidine, or famotidine as alternative choices.
SSRIs: Fluvoxamine interacts significantly, while paroxetine, fluoxetine, and sertraline do not. Miscellaneous agents: Allopurinol, disulfuram, mexiletine, pentoxifylline, propafenone, tacrine, thiabendazole, ticlopidine, verapamil, and zileuton.
Blood levels are gradually decreased by these enzyme inducers:
Anti-epileptic agents: Barbiturates, carbamazepine, phenytoin, and primidone.
Anti-mycobacterial agents: Rifabutin, and rifampin. Glutethimide and aminoglutethimide.S

     Corticosteroids in COPD are also a controversial issue; and here again, efficacy improves as the level of asthma involvement increases and even acute exacerbation. As inflammatory factors in the pathogenesis of COPD become more evident, the role of long-term suppression of inflammation in preventing disease progression may be redefined;N but clinical benefit in the COPD patient is limited. When utilized for refractory cases that perhaps fail to respond to bronchodilator therapy or in acute exacerbation,1 40mg per day of prednisone tapered as soon as practical may be tried, with eventual change to MDI administration to limit side effects. As with the various bronchodilator therapies, if no benefit is seen, corticosteroids should be discontinued.2
      In cases of congenital AAT deficiency (PiZZ phenotype), Prolastin(TM) (human alpha-1 proteinase inhibitor) in a regimen of 60mg/kg IV once weekly can prevent exacerbation of panacinar emphysema. Studies are underway to evaluate nebulizer administration; improvement of symptoms has been noted in PiZZ patients with atopic asthma, especially with concurrent use of antileukotrienes.O
     Current research efforts are also evaluating the use of retinoic acid, particularly all-trans retinoic acid (ATRA) in COPD. Evidence in animal studies shows that ATRA actually causes growth of new alveolar tissues and alveoli – actually reversing the damage done by emphysema. U,V

Supplemental Oxygen
     Though home administration of oxygen to the patient recovering from acute exacerbation or to alleviate exercise-induced dyspnea has not been shown to improve survival or even speed recovery, it can make the patient more comfortable. Chronic hypoxemia, though, causes irreversible pulmonary vasoconstriction to further limit perfusion capacity and eventually lead to cor pulmonale and increased mortality. Regular administration of oxygen for periods of 15 hours or more per day to the patient with severe chronic hypoxemia has been shown to significantly reduce progression of COPD. Studies indicate that long-term administration must continue for at least six months at least 15 hours per day to produce any significant reduction in progression rate or mortality. Overnight administration while the patient sleeps is insufficient.2

References
Chronic Obstructive Pulmonary Disease. Chest Medicine Online. http://www.priory.com/cmol.diagnosi.htm. 4/18/99.

Hafner, J. Ferro, T. Recent Developments in the Management of COPD. Hospital Medicine 34(1):29-30, 32-38, 1998. Smirniotopoulos, J. COPD – Chronic Obstructive Pulmonary Disease. Tabular Discussion for Electronic Systems. http://radlinux1.usuf1.usuhs.mil/ms2radpath/copd001.html.

Cavarra E; Martorana P; Gambelli F; de Santi M; van Even P; Lungarella G. Neutrophil recruitment into the lungs is associated with increased lung elastase burden, decreased lung elastin, and emphysema in alpha 1 proteinase inhibitior-deficient mice. Lab Invest 1996 Aug; 75(2): 273-80.

Emphysema Facts. http://www.nhlbi.nih.gov/nhlbi/infcntr/topics/emphyse.htm. 4/21/99

Jacobs M. The Office Management of Obstructive Lung Disease. http://www-med.stanford.edu/school/DGIM/Teaching/Modules/copd.html. 4/6/99

Shteyngart B, Chaiwiriyakul S, Wong j, Cantor J. Preferential binding of lysozyme to elastic fibres in pulmonary emphysema. Thorax 1998 Mar 53:3 193-6.

Ofulue A, Ko M, Abboud R. Time course of neutrophil and macrophage elastinolytic activities in cigarette smoke-induced emphysema. Am J Physiol 1998 Dec 275:6 Pt 1 l1134-44.

van Straaten J, Postma D, Coers W, Noordhoek J, Kauffman H, Timens W. Macrophages in lung tissue from patients with pulmonary emphysema express both inducible and endothelial nitric oxide synthase. Mod Pathol 1998 Jul 11:7 648-55.

Wiebe B, Laursen H. Lung morphometry by unbiased methods in emphysema: bronchial and blood vessel volume, alveolar surface area and capillary length. APMIS 1998 Jun 106:6 651-6.

Sexton W, Poole D. Effects of emphysema on diaphragm blood flow during exercise. J Appl Physiol 1998 Mar 84:3 971-9.

K. Gelb A, Zamel N, Hogg J, Muller N, Schein M. Pseudophysiologic emphysema resulting from severe small-airways disease. Am J Respir Crit Care Med 1998 Sep 158:3 815-9.

N Early Identification and Active Intervention Essential in the Long-term Management of Stable COPD. Drug & Ther Perspect 12(11):5-8, 1998.

Eden, E. Alpha-Antitrypsin Deficiencey in COPD: Clinical Implications. Medscape Respiratory Care. http://wwww.medscape.com/Medscape/RespiratoryCare/journal/1998/v02.n.../mrc3114.eden.htm. 4/25/99

Douglas, J. Crriel, D. Gene Therapy for Inherited, Inflammatory and Infectious Diseases of the Lung. Medscape Respiratory Care. http://wwww.medscape.com/Medscape/RespiratoryCare/journal/1998/v02.n0.../mrc4574.curi.htm. 4/25/99

Ferguson G, Cherniack R. Management of Chronic Obstructive Pulmonary Disease. NEJM 1993 apr 328: 1017-1022. Hansten P, Horn J. Clinically Important Drug Interactions: 1998. Drug Interactions Analysis and Management. 1998