Chronic Obstructive Pulmonary Disease: Emphysema Revisited

Nhue L. Do and Beek Y. Chin

Beth Israel Deaconess Medical Center

Harvard School of Medicine

Center for Life Sciences

Boston, MA

USA

1. Introduction

     The chronic obstructive pulmonary disease (COPD) encompasses two phenotypically related diseases, chronic bronchitis and emphysema [1-2]. Although the hallmark of COPD is inflammation and inability to maintain efficient gas exchange, emphysema is often characterized by atypical over-distension of the alveoli and permanent destruction of the surrounding supporting structures leading to irreversible damage to gaseous exchange. Statistically, it is rapidly approaching a leading cause of mortality in the United States [3], with a morbidity of 4.9 million [4] and mortality rate at 4.2 per 100,000 [5]. Even with a higher prevalence of COPD related incidences in chronic bronchitis, mortality from emphysema (12,790) had exceeded that of chronic bronchitis (667) in pulmonary-related deaths [5] making early diagnosis and treatment of emphysema an alarming and continued cause for concern.

2. Pathogenesis of emphysema

       The pathogenesis of emphysema is embodied by enlargement of alveolar space, progressive destruction of connective tissue and loss of elasticity leading to eventual collapse of the small airways and destruction of pulmonary-alveolar units, all of which combine to limit gas exchange and airflow out of the lungs. These physical manifestations are usually initiated by chronic inflammation and induction of persistent oxidative stress mediated primarily by the neutrophil, a key innate immune cell residing in the

conducting airways [6]. The persistent thought for the past four decades was that the

tenuous balance between proteases and anti-proteases determined the severity of airway

damage and alveolar enlargement, with the main protease-inhibitor, alpha1 anti-trypsin

(AAT1) [6] severely lacking to combat the secretagogue elastase, from the chronically

activated resident neutrophils [7-8]. Activated neutrophils also promote the secretion of

mucus and inhibit the clearance ability of mucocilliary cilia thus adding to the severity of

disease.

 Corresponding Author

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The role of another innate cell, the alveolar macrophage which resides in the alveolar

region [9-10] has been demonstrated to be markedly influenced by the pro-inflammatory

milieu and also promote the secretion of elastase [11] primarily matrix-metalloproteases

(MMP), and key cytokines/chemokines responsible for sustaining inflammation and

inhibition of the healing or resolution process [11]. Of all the MMP implicated, MMP-9

was demonstrated to be markedly elevated in patients with emphysema [12-13]. Even

though MMP-9 is capable of breaking down extra cellular matrices and cause destruction

of the septal and alveolar walls, recent evidence has questioned its role [14-15] suggesting

that some of the MMP may not be directly associated with the progression of disease as

inhibiting the expression does not affect the severity in smoke-induced emphysema in

rodents.

A majority of recent documented emphysema cases is primarily attributed to inhalation of

damaging stimuli such as cigarette smoke (CS) [16]. The emergent contribution of oxidants

is integral to the development of emphysema. CS either in the form of chronic smoking or in

the laboratory to induce experimental-emphysema in rodents, consists of both reactive

oxygen and reactive nitrogen species, both of which are robust inducers of inflammation

[17]. Additionally, other components of CS such as particulate matter, in itself a potent

activator of macrophages [18-19], is able to induce the generation of macrophage-derived

oxidants, thus adding to the persistence of a pro-inflammatory milieu. These CS- and

macrophage-derived oxidants can contribute to the inactivation of AAT1, promote the

activation of MMP and impair the pulmonary-alveolar units (PAU) in situ, therefore

exaggerating the already compromised situation [20]. Another index of emphysema which

has recently emerged is the increased pulmonary capillary endothelial cell turnover as a

direct result of the destruction of the PAU [21], resulting in the elaboration of endothelial

microparticle (EMP). Using stringent criteria to determine the source of PAU, the authors

confirmed that emphysematous patients have increased circulating plasma levels of

pulmonary capillary endothelium-derived EMP as a result of increased endothelial

turnover. They also added that the detection of EMP in the plasma superseded any

spirometry evidence of emphysema, thus adding an early novel albeit invasive biomarker of

emphysema.

There are three major causative factors for the development of emphysema;

environmental, social and genetic predisposition. Coal miners and those working with

silica often inhale airborne toxicants that contribute to initial oxidative stress [22]. It is the

inability to remove these toxicants that lead to progressive inflammation and destruction

of respiratory tissue. In addition to the anti-protease role of AAT1, recent evidence

documenting the role of AAT1 as an anti-inflammatory protein [reviewed in 23] only

highlights the importance of those who inherited this deficiency. The influence of

smoking or ‘inhalation of toxicants by choice’ remains a controversial and somewhat

contentious causative factor of emphysema. However, the combination of AAT1

deficiency and chronic smoking or coal miners who are heavy smokers almost always

result in the progressive development of emphysema.

3. Presentation of COPD: Emphysema

Chronic obstructive pulmonary disease (COPD) has significant impact on not only patients

inflicted with the disease but also on the healthcare system under which they are taken care of.

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Patients with severe COPD have significant physical impairment with reduction in quality

of life and can result in death. The healthcare system requires that patients have multiple

office visits and frequent hospitalizations on top of chronic lifelong therapy that includes

medications and long-term oxygen treatments. Early diagnosis of COPD can help early

management of symptoms and make lifestyle changes such as the cessation of smoking, as

ultimately these practices are the only options to slowing the progression of disease.

However, this disease is still underdiagnosed with only 15% of smokers diagnosed with

COPD [24].

Patients with emphysema can have varying degrees of symptoms ranging from few to

chronic respiratory complaints with acute exacerbations. Some symptoms include dyspnea,

cough, wheezing, and acute chest illnesses. Any patient with a chronic cough, dyspnea or a

history of any exposure to risk factors such as CS, occupational dusts, chemicals and smoke

from home or heating fuels should have the diagnosis of emphysema suspected for their

symptoms [25]. Some patients may unknowingly restrict their own activities since

emphysema is slowly progressive and persistent. Physical examination findings are usually

only present in patients with severe disease which includes, over distention of the lungs in

the stable state with the chest held near full inspiratory position at the end of normal

expiration, and a low diaphragmatic position resulting in retraction of the lower intercostal

spaces (Hoover’s sign) [26]. Additionally, there is decreased intensity of breath and heart

sounds accompanied by a prolonged expiratory phase [27]. Wheezes on auscultation on

slow or forced breathing with a prolongation of forced expiratory time may be evidence of

airflow obstruction. Some of the frequently classically described characteristics include

purse-lip breathing, accessory respiratory muscle usage of the neck and shoulder girdle

muscles. Other findings may be unusual positions to relieve dyspnea such as leaning

forward with arms outstretched (tripod position) [28], digital clubbing, dependent edema in

the absence of right heart failure, neck vein distention and an enlarged liver due to right

heart failure.

Patients with suspected emphysema may present at various stages of the disease process.

Chest radiography is usual the initial study performed or ordered but will not be diagnostic

except in severe cases, however, is still important to exclude other lung diseases. Signs of

hyperinflation on the chest radiograph include; rapidly tapering vascular shadows with

increased radiolucency of the lung, a flat diaphragm and a long narrow heart shadow on

posterior-anterior films and flat diaphragmatic contour and increased retrosternal airspace

on a lateral radiograph (Figure 1a-b). Bullae may also be identified on a chest radiograph.

Computed tomography (CT) is better able to characterize the involvement pattern as either

centriacinar or panacinar. Centriacinar usually involves the upper lobes in the center of

secondary pulmonary lobules, in contrast to panacinar with involves the lung bases and the

entire secondary pulmonary nodule with generalized paucity of the vascular structures. CT

has become the mainstay in evaluating patients for lung volume reduction surgery [29-30].

Pulmonary function tests (PFTs) have become the cornerstone of the diagnostic evaluation

of patients because these patients may be symptomatic but have no physical exam findings

[31]. PFTs can determine the severity of the airflow obstruction and can also be used to

follow the disease progression, with spirometry being the essential confirmatory test that

not only stages COPD but also distinguishes the phenotype of COPD [32]. The forced

expiratory volume in one second (FEV1) and forced vital capacity (FVC) is needed to

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Fig. 1a. Schematic of typical anteroposterior

Fig. 1b. Lateral chest radiograph findings of emphysema.

establish the presence of obstruction, with a ratio of less than 0.70 being significant for

obstruction [33]. The inspiratory capacity is usually decreased with tachypnea due to

dynamic hyperinflation and increased total lung capacity, functional residual capacity and

residual volume. The measurement of carbon monoxide diffusing capacity can help to

establish the presence of emphysema but is not used in the routine diagnosis of COPD.

Arterial blood gases (ABG) is used to correlate symptoms with blood oxygenation levels but

is not needed in mild to moderate airflow obstruction. ABG is optional in moderately severe

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airflow obstruction however, for severe disease, ABG then becomes the major monitoring

tool once hypoxemia with hypercapnia develops.

4. Treatment of emphysema

The treatment of pulmonary emphysema has not only puzzled surgeons but has also

attracted their interest throughout history. Many operations have been proposed however, it

was not until further understanding of the physiological impairment of the disease was

understood that appropriate surgical treatment evolved. Surgical treatment for patients on

maximal medical therapy but remain symptomatic carries both morbidity and mortality;

however, the operations also carry with them the hope of relief from dyspnea. Three typical

operations performed for emphysema are bullectomy, volume reduction, and lung

transplantation.

4.1 Bullectomy

Bullae are defined as emphysematous spaces larger than 1 cm in diameter in the inflated

lung, usually demarcated from surrounding lung tissue and pathologically consists of

enlarged airspaces covered by visceral pleural. Bullae have been characterized into three

different types with Type I and II associated with diffuse emphysema, with type III

representing complete loss of parenchymal architecture throughout lung fields [34]. Bullae

in emphysematous disease is believed to arise via a ball-valve mechanism where air is

allowed to enter the airspace but not allowed to escape with progressive enlargement of the

airspace over time [35-36]. The enlarged space-occupying lesion leads to compression of the

surrounding emphysematous lung tissue with preferential filling of the bullae, when

exposed to the same negative intrapleural pressure results in continued enlargement [37-39].

The indication for a bullectomy is to permit expansion of the previously collapsed

surrounding lung tissue to regain function as well as restore physiologic respiratory

function [40]. Compression of surrounding lung tissue by bullae impairs overall gas

exchange due to low ventilation to perfusion ratios in the compressed lung region.

Furthermore, bullae can result in increased intra-thoracic pressures eventually resulting in

hemodynamic dysfunction from compression of the pulmonary arterial system, decrease in

systemic venous return, and increased expiratory airway resistance [40]. Large bullae my

also restrict the function of the diaphragm and the thoracic chest wall muscles. Bullectomy

would remove the space-occupying lesion, reduce expiratory airway resistance, and reduce

dead-space ventilation that may result in overall improvement in respiratory function.

The benefit of a bullectomy must be determined based on careful selection of individuals

based on the size of the bullae, the degree of compression and whether underlying condition

of compressed lung parenchyma exists [42-45]. The highest predictor for benefit from a

bullectomy is that young individuals with large localized unilateral bullae that are

nonventilated, nonperfused, with significant compression of surrounding lung tissue that

has good perfusion and early emphysema [43]. Although posteroanterior and lateral

radiographs can identify bullae, CT has become the mainstay imaging technique in

delineating the anatomy of bullae [46]. The operative approach for bullectomy is variable

and is dependent on the anatomic details of the bullae and specific techniques deployed by

the surgeon in question. Single large bullae with a small pedicle may be excised using either

a muscle-sparing thoracotomy or a video-assisted thorascopic surgery (VATS), and resected

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with a stapler (Figure 2). In some instances, large bullae may have completely destroyed an

entire lobe requiring lobectomy.

Fig. 2. VATS stapled bullectomy.

Mortality rates of bullectomy should range from 1 to 5%. The mortality rate of

approximately 2.3% in well-selected patients was established more than 30 years ago by

Fitzgerald et al with similar results in modern studies [42, 47]. Similar rates have been seen

in patients undergoing VATS compared to thoracotomy approaches. Delayed expansion of

the remaining lung tissue, parenchymal air leaks and pulmonary infections are some known

post-operative complications, with air leaks being the most frequently occurring. Persistent

air-leaks can be managed with the use of a Heimlich valve [48]. Results from bullectomies

are difficult to analyze given that there are no prospective randomized clinical trials

comparing medical therapy with surgery, as all previous studies were retrospective case

series. The most recent series by Schipper et al looking at intermediate- to long-term results

showed improvement in functional status up to 3 years after resection of giant bullae [47].

4.2 Lung volume reduction (LVR)

Lung volume reduction (LVR) is similar to bullectomy, the difference being that LVR is an

extension performed for diseases that affect the entire lung. LVR was pioneered by Otto

Brantigan in the 1950s but was not adopted due to a high mortality rate of 18% [49].

Brantigan’s initial hypothesis was that the diseased portions of the lung resulted in loss of

elasticity and that removing the most diseased portions permitted and maintained patency

of the remaining bronchioles to improve airflow [49]. It was not until several decades later

that Delarue et al [50] and Dahan [51] et al re-introduced the concept in patients with endstage

emphysema. However, the role of LVR would not become popular until 1994 when

Cooper [52] adapted Brantigan’s initial concept. The underlying pathology of end-stage

emphysema is characterized by distended airspaces that are inadequately ventilated but

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with continued perfusion (ventilation-perfusion mismatch) nevertheless, resection of the

diseased portions would result in improved ventilation to other functional regions. LVR also

serves to re-establish normal chest wall dynamics and may result in improvement in

hemodynamic function from the lowering of intra-thoracic pressure throughout the

respiratory cycle.

Selection of candidates for LVR is dependent on the anatomic characteristics of the diseased

portion of the lung with ideal candidates having heterogeneous upper-lobe involvement

[53]. There is less dramatic improvement in candidates undergoing LVR with lower lobe

involvement [54]. Patients being considered for LVR usually undergo scintigrams to identify

potential targets for resection. The most important factor for success of LVR has been the

meticulous selection of patients based on the National Emphysema Treatment Trial or NETT

criteria [55]. Again CT has become the mainstay for characterization of possible resection

margins. The mortality rate ranges from 0 to 7.5% with varying surgical approaches [52, 56-

58]. Multiple approaches have been used including median sternotomy, bilateral

thoracotomies or VATS (Figure 3). All have similar results with functional improvement

disappearing over a period of 3 to 5 years, but LVR patients continue to have a clinical

advantage over medical treatment for those 3-5 years with substantial gains in exercise

tolerance, freedom with oxygen therapy, and overall improvement in quality of life. The

most significant trial, NETT, reported the results which included 1218 patients randomized

between LVRS and medical therapy between January 1998 and July 2002 [59]. This trial

reported a 90-day surgical mortality of 7.9% without a significant difference in surgical

approach. Patients with upper-lobe predominant emphysema had a greater survival benefit

from surgery while those with lower-lobe predominant emphysema demonstrated survival

benefits from medical therapy. Based on these promising results, LVR can be performed for

patients who are not candidates for lung transplant.

Fig. 3. VATS lung volume reduction surgery for upper-lobe predominant emphysema.

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A new technique of lung volume reduction with less morbidity and mortality compared to

surgical LVR is bronchoscopic lung volume reduction (LVR). Bronchoscopic LVR aims to

achieve the same goals as LVRS: improve physiologic mechanics of the chest wall and

diaphragm, restore ventilation-perfusion matching, and improve expiratory airflow. The

method by which this is achieved is through the use of a bronchoscope to deploy one-way

valves, administer sealants, or apply thermal ablation to exclude diseased portions of the

lung [60-62]. It is important to note that these techniques have not been approved by the

Food and Drug Administration (FDA) for the treatment of severe emphysema and are

currently utilized on experimental basis only. The most developed and well-studied of the

bronchoscopic techniques is the one-way valve. One-way valves allow air and mucus to

escape from the excluded portion of lung yet concomitantly excluding that portion of the

lung from normal physiological function. [61] Multiple valve designs have been tested, the

largest on which was the Endobronchial Valve for Emphysema Palliation Trial (Figure 4)

(VENT) [63-64] There was significant improvement in dyspnea, exercise capacity, and

quality of life but not as significant as that which is seen in LVRS. [64]. Possible explanations

for the minor improvement seen compare to LVRS have been attributed to collateral

ventilation through incomplete lobar fissures. There were more complications of pneumonia,

hemoptysis, and pneumothorax in the treatment group, all of which would be expected from

an invasive procedure. [64]. The administration of sealants is far less developed and studied

when compared to that of one-way valves, and includes the use of fibrin-thrombin mixtures to

create a scaffold for collagen deposition by fibrblasts [65]. Preliminary studies show minor

improvements in pulmonary function tests but no significant clinical benefits [66-67].

Fig. 4. Endobronchial lung volume reduction with one-valve for lower-lobe predominant

emphysema.

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Thermal ablation is the least developed and studied of the bronchoscopic LVR techniques.

The use of heated vapor to induce an inflammatory response resulting in occlusion of a

diseased portion of lung has only been tested in feasibility studies with further exploratory

efforts required due to small sample sizes [68]. Although bronchoscpoic LVR is an emerging

technique, further analyses as well as long-term follow-up studies are needed.

4.3 Lung transplantation

Lung transplantation was originally thought to not be a feasible treatment for emphysema.

It wasn’t until after the seminal transplantation of single lungs demonstrating significant

improvement in symptoms, that lung transplantation became a mainstay for the end-stage

emphysema [69-71]. Currently, the most common indication for lung transplantation is

idiopathic diffuse emphysema and AAT1 deficiency, two criteria that account for the

majority of lung transplants [70]. Lung transplant patients are usually so critically ill that the

risk of death from their lung disease enables the actual lung transplant operation to appear

quite equitable. The advantages of a lung transplant result in complete replacement of the

diseased lung with significant improvements in symptoms [72]. There are however,

significant disadvantages to lung transplantation including higher mortality (5 to 15%),

lifelong immunosuppression resulting in risks of serious infection and rejection with a

cumulative survival rate of around 50% [73-74].

5. Summary

Emphysema can be a preventable and equally treatable pulmonary disease. With the advent

of new diagnostic criteria such as the emergence of a key biomarker, circulating levels of

EMP may lead to efficient diagnosis and preventative care. Patients with emphysema can

present a varying array of symptoms and physical examination findings. While the majority

of patients can be managed with medical therapy, those who continue to progress may

require surgical intervention based on their diagnostic studies. The ideal surgical treatment

of emphysema is dictated by a rigorous selection criteria for each of the possible

interventions described and can dramatically improve the quality of life of individuals

inflicted with this disease. New and innovative methods for treating crippling emphysemic

patients who are not candidates for surgical treatments include bronchoscopic placement of

one-way valves into diseased segments of lung tissue or airway bypass by means of

inserting stents between bronchi and adjacent lung tissue [75-78], however, these emergent

techniques necessitate further exploratory and long term studies.

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Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

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Chronic Obstructive Pulmonary Disease - Current Concepts and

Practice

Edited by Dr. Kian-Chung Ong

ISBN 978-953-51-0163-5

Hard cover, 474 pages

Publisher InTech

Published online 02, March, 2012

Published in print edition March, 2012

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A decade or so ago, many clinicians were described as having an unnecessarily 'nihilistic' view of COPD. This

has certainly changed over the years... This open access book on COPD provides a platform for scientists and

clinicians from around the world to present their knowledge of the disease and up-to-date scientific findings,

and avails the reader to a multitude of topics: from recent discoveries in the basic sciences to state-of-the-art

interventions on COPD. Management of patients with COPD challenges the whole gamut of Respiratory

Medicine - necessarily pushing frontiers in pulmonary function (and exercise) testing, radiologic imaging,

pharmaceuticals, chest physiotherapy, intensive care with respiratory therapy, bronchology and thoracic

surgery. In addition, multi-disciplinary inputs from other specialty fields such as cardiology, neuro-psychiatry,

geriatric medicine and palliative care are often necessary for the comprehensive management of COPD. The

recent progress and a multi-disciplinary approach in dealing with COPD certainly bode well for the future.

Nonetheless, the final goal and ultimate outcome is in improving the health status and survival of patients with

COPD.

How to reference

In order to correctly reference this scholarly work, feel free to copy and paste the following:

Nhue L. Do and Beek Y. Chin (2012). Chronic Obstructive Pulmonary Disease: Emphysema Revisited, Chronic

Obstructive Pulmonary Disease - Current Concepts and Practice, Dr. Kian-Chung Ong (Ed.), ISBN: 978-953-

51-0163-5, InTech, Available from: http://www.intechopen.com/books/chronic-obstructive-pulmonary-diseasecurrent-

concepts-and-practice/chronic-obstructive-pulmonary-disease-emphysema-revisited