**6. Natural history of disease**

The natural history of COPD as we know, is based on multiple longitudinal studies, although most spanned much shorter duration than the actual length of disease progression(Rennard & Vestbo,2008 as cited in Shapiro SD,2010). The classic study of Fletcher and colleagues and extrapolation of the data of other studies have yielded the "Fletcher-Peto curve," which is basically a plot of FEV1 versus age (Fletcher,1976). The curve describes the gradually progressive permanent loss of lung function as age advances. Although it doesn't include the concept of COPD in non-smokers and extrapulmonary effects of COPD, it serves a basic guide to understand the clinical course of the disease.

The normal (M) alleles are found in about 90% of persons of European descent with normal serum A1PI levels(150 to 350 mg/dL or 20 to 48 µmol/dL); their phenotype is designated Pi MM. More than 95% of persons in the severely deficient category are homozygous for the Z allele(Pi ZZ) and have serum A1PI levels of 2.5 to 7 µmol/dL (mean, 16% normal)with an estimated prevalence between 1 in 1600 to 1 in 4000.This allele is mostly found in whites of

Rarely observed phenotypes associated with low levels of serum A1PI include the following: Pi SZ and persons with nonexpressing alleles; Pi null, found in homozygous form as Pi null-null and found in heterozygous form with a deficient allele as Pi Z null. Persons with phenotype Pi SS have A1PI values ranging from 15 to 33 µmol/dL (mean, 52% of normal). The threshold protective level of 11 µmol/dL (35% of normal) is based on the knowledge that Pi SZ heterozygotes, with serum A1PI values of 8 to 19 µmol/dL (mean, 37% of normal), rarely develop emphysema. Pi MZ heterozygotes have serum A1PI levels that are intermediate between Pi MM normals and Pi ZZ homozygotes (12–35 µmol/dL; mean, 57% of normal). There appears to be a small increase in risk of COPD in all Pi MZ

COPD in homozygous A1PI deficiency patients is characterized by premature development of severe panacinar emphysema usually in the basilar regions of lung (Silverman & Sandhaus,2009). The onset of dyspnea occurs at a median age of 40 years about 1-2 decades earlier than rest of the population(Silverman & Sandhaus,2009 as cited in Shapiro SD,2010). However smoking has supradditive effect on poorer prognosis both with earlier onset severity and poorer prognosis of the disease(Janus et al,1985 as cited in Shapiro SD,2010). Radiographically, disease is more prominent in PiZZ patients and worse in basilar regions, sometimes hairline arcuate shadows separating markedly radiolucent areas in the lung bases from the less severely involved upper portions of the lungs (Gishen et al,1982;Hepper

A1PI deficiency is diagnosed by measuring the serum A1PI level, followed by Pi typing for confirmation. However, by the time they develop COPD symptoms, they already have significant liver disease often diagnosed in infancy/childhood with hepatomegaly or hepatosplenomegaly and evidence of cholestasis and elevation of hepatocellular enzymes. Screening for PiZZ in COPD patients is not recommended at present. Augmentation therapy with A1PI supplementation has been proposed for COPD patients with PiZZ genotype as

The natural history of COPD as we know, is based on multiple longitudinal studies, although most spanned much shorter duration than the actual length of disease progression(Rennard & Vestbo,2008 as cited in Shapiro SD,2010). The classic study of Fletcher and colleagues and extrapolation of the data of other studies have yielded the "Fletcher-Peto curve," which is basically a plot of FEV1 versus age (Fletcher,1976). The curve describes the gradually progressive permanent loss of lung function as age advances. Although it doesn't include the concept of COPD in non-smokers and extrapulmonary effects of COPD, it serves a basic guide to understand the clinical course

northern European descent.

et al,1978 as cited in Shapiro SD,2010).

per guidelines issued by ATS(ATS,1995)

**6. Natural history of disease** 

of the disease.

individuals.

The natural history of COPD probably starts at pre-conception age related to genetics and intra-uterine lung development and growth, extending into early life events such as childhood and adolescent lung growth and injury from infections as well as later events such as adult lung exposures to cigarette smoke and occupational inhalants.

Since the disease progresses slowly over the years, the earlier stages of the disease are often "silent" and mostly unnoticed by the patient. Exertional dyspnea, the earliest symptom, primarily from dynamic hyperinflation from exercise induced tachypnea, results in subconscious preferential sedentary lifestyle and thus avoiding the symptoms till later stage.(O'Donnell et al.,2001 as cited in Shapiro SD,2010)

The intrauterine growth of lung includes development of conducting airways, gas exchange structures, including respiratory bronchioles and alveoli, but branching of alveolar wall continues postnatally for several years and usually complete by the first decade of life(Ten Have-Opbroek,1981 as cited in Shapiro SD,2010). Subsequent growth of the lung is due to increase in alveolar size and increase in airway diameter, but not in number. Maximal lung function is attained in young adulthood and remains relatively constant as a plateu for some years before declining in a slowly accelerating manner in older age(Weiss & Ware,1996 as cited in Shapiro SD,2010). The decline averages 20 mL/yr increasing in an accelerating manner and by age 50, there is an average drop of FEV1 by 1L.

Smoking adversely affects the entire course, with interference in maximal lung capacity attainment if smoking starts in the early growth phase, to shortening of duration of the plateu phase, to rapid decline in lung function in later age(Burrows,1990 as cited in Shapiro SD,2010). This effect is very well depicted in the "Fletcher-Peto curve" shifting the plot downwards and earlier in age (Fletcher, 1976). The average COPD patient who smokes loses almost twice the lung function than usual(about 2 L of FEV1 over 50 years, an average decline of about 40 mL/yr). Acute exacerbations have descending step-ladder like effect with acute drops over short period with incomplete recovery resulting in faster drop of lung function(Burrows,1990 as cited in Shapiro SD,2010). Smoking has a predictable dosedependent deleterious effect on the lung function and cessation of smoking has beneficial slowing of disease progression if initiated early enough in course of disease (Anthonisen et al,1994;Buist et al.,1976 as cited in Shapiro SD,2010).

Some individuals experience a rapid decline in lung function (Gottlieb et al.,1996 as cited in Shapiro SD,2010). Faster decline in lung function is noted in patients with low baseline lung function, less reversibility to β2-agonists, more severe bronchial hyperresponsiveness, mucus production, male sex, and frequent exacerbations(ATS,2010). Identification of slow and rapid decliners in longitudinal studies such as the Lung Health Study has allowed exploration of biomarkers to characterize these groups. Importantly, systemic markers of inflammation have been associated with poorer lung function, and, in some, studies, with an increased rate of decline in lung function (Fogarty et al.,2007;Shaaban et al.,2006; Sin & Man,2003 as cited in Shapiro SD,2010).

Although early stage COPD is difficult to diagnose, newer studies have shown a poorer prognosis among these population primarily from adverse cardiac events (Ashley et al., 1975; Mannino et al., 2003 as cited in Shapiro SD,2010). The cardiac events may be linked to the extrapulmonary effects of COPD, especially elevated systemic inflammatory mediators. Identifying and treating this group thus can have valuable prognostic benefit.

Current Overview of COPD with Special Reference to Emphysema 133

and followed by prolonged recovery over months and may be difficult to distinguish from other causes of dypsnea, cough, and/or sputum including pneumonia, congestive heart failure, pulmonary embolism, or pneumothorax(Spencer & Jones,2003 as cited in Shapiro

A history of cigarette smoking or alternative inhalational exposure is usually found in majority of COPD patients. A1PI deficient patients may develop disease without smoking, however presence of smoking significantly worsens the course of disease. Some patients develop COPD without an obvious risk factor. Other historical features that may accompany COPD include certain comorbidities (eg, lung cancer, coronary artery disease, osteoporosis, depression, skeletal muscle weakness). Although most patients are usually obese, weight

Physical findings in early COPD is highly non-specific and unreliable. Early stage patients may have coarse crackles and rhonchi. Wheezing may be found occasionally especially

The hallmark finding is obstruction of expiratory airflow. Measurement of the forced expiratory time maneuver is a simple bedside test and most consistent finding in symptomatic COPD. A forced expiratory time greater than 4 seconds indicates severe expiratory airflow obstruction. Objective measurement of airflow by spirometry, which is simple and accurate forms the basis of staging and follow-up of disease

As the airway obstruction worsens, physical examination may reveal hyperinflation, decreased breath sounds, wheezes, crackles at the lung bases, and/or distant heart sounds. In addition, the diaphragm may be depressed and limited in its motion, and the

Patients with end-stage COPD may present with barrel-shaped chest, increased span of hyperresonant lung percussion, distended neck veins, full use of the accessory respiratory muscles of the neck and shoulder girdle, purse-lipped breathing, paradoxical retraction of the lower interspaces during inspiration (ie, Hoover's sign), emaciation, and frequently, inguinal hernias. They may adopt positions that relieve dyspnea, such as leaning forward with arms outstretched and weight supported on the palms(Tripod sign). This position stabilizes the shoulder girdle and helps to maximize intrathoracic volume. Late signs may include cyanosis, clubbing, asterixis due to severe hypercapnia, and an enlarged, tender

Pneumothorax can precipitate severe dyspnea and acute respiratory failure and may be life threatening since they have only a marginal pulmonary reserve. Presence of giant bullae as part of disease predisposes to this complication. It can be difficult to treat if accompanied by a persistent air leak between the involved lung and the pleural space (bronchopleural

loss can also occur in COPD and is associated with a worse prognosis.

SD,2010).

**7.2 Physical findings** 

progression(Petty,2001).

liver due to right heart failure.

**8. Complications of COPD** 

**8.1 Pneumothorax** 

fistula).

associated with asthma or acute exacerbations.

anteroposterior diameter of the chest may be increased.

With advanced disease, obvious exertional dyspnea, cough and frequent acute exacerbations dominate the picture. Morbidity and mortality increases with declining FEV1. Primary cause of mortality is cardiac events, however with advanced age and disease, pulmonary complications causing death, increase in proportion. Each exacerbation and the following recovery stage makes the patient most vulnerable to adverse outcomes as shown by the SUPPORT (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments), which demonstrated a 49% 2-year mortality rate after hospital admissions with COPD exacerbation with CO2 retention(Connors et al.,1996).

Various therapeutic and supportive medical and surgical intervention combined with rehabilitative measures help in alleviation of symptoms, slowing of pace of progression of disease and reduction of disability. Individualized plans for each patient based on the characteristic and stage of disease is important to achieve optimal results.
