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ScienceWeek
MEDICAL BIOLOGY: ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE
The following points are made by E.R. Sutherland and R.M. Cherniack (New Engl. J. Med. 2004 350:2689):
1) Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma.(1) The primary physiological abnormality in COPD is an accelerated decline in the forced expiratory volume in one second (FEV1) from the normal rate in adults over 30 years of age of approximately 30 ml per year to nearly 60 ml per year.(2) The disease course begins with an asymptomatic phase in which lung function deteriorates without associated symptoms. The onset of the subsequent symptomatic phase is variable but often does not occur until the FEV1 has fallen to approximately 50 percent of the predicted normal value.(3) Since substantial deterioration in airflow has already occurred by the time most patients present with symptoms, it is reasonable to conclude that the degree of airflow limitation is only one of many factors that govern the onset of symptoms.
2) Hyperinflation, which occurs at rest and worsens with exercise, is an additional physiological abnormality that is commonly seen in patients with moderate-to-severe COPD. It is manifested primarily by an increase in the functional residual capacity, which places the muscles of respiration at a mechanical disadvantage, thereby increasing the work of breathing and reducing exercise tolerance. Additional physiological abnormalities include a reduction in the diffusing capacity for carbon monoxide, hypoxemia, and alveolar hypoventilation.
3) Because the majority of cases occur in patients who have smoked,(4) all current or former smokers should be considered at increased risk for COPD. Other risk factors, which account for far fewer cases, include 1-antitrypsin deficiency(5), airway hyperresponsiveness, and indoor air pollution. Since symptoms may not occur until lung function is substantially reduced, early detection is enhanced by spirometric evaluation of FEV1 and forced vital capacity (FVC). Guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) state that the airflow limitation in COPD is characterized by an FEV1 value that is less than 80 percent of the predicted normal value and an FEV1:FVC ratio of less than 0.70.(3)
4) Currently, most guidelines recommend that practitioners use a combination of information about symptoms and evidence of impairment of physiological function in determining the severity of the disease(3), although the guidelines differ somewhat with regard to setting thresholds for mild, moderate, and severe disease. The stage of the disease suggests the prognosis, and follow-up data from longitudinal studies indicate that moderate and severe stages of the disease are associated with higher mortality. However, in the largely asymptomatic group of patients that GOLD3 categorizes as "stage 0, at risk", only 18.5 percent of the patients progress to more severe airflow limitation at 15 years, which suggests that more information is required to predict which patients with incipient disease will progress rapidly to a more advanced stage.
References (abridged):
1. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166:675-679
2. Fabbri LM, Hurd SS. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur Respir J 2003;22:1-2
3. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977;1:1645-1648
4. Eriksson S. Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl 1965;432:1-85
5. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153:1802-1811
New Engl. J. Med. http://www.nejm.org
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MEDICAL BIOLOGY: CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Notes by ScienceWeek:
Chronic obstructive pulmonary disease (COPD) is more a constellation of symptoms than a single disease entity with a specific etiology, associated specific symptoms, and specific anatomic changes. In general, the disorder is characterized by the progressive development of lung airflow limitation that is not fully reversible. The term "chronic obstructive pulmonary disease", according to one scheme, encompasses chronic obstructive bronchitis, with obstruction of small airways in the lung, and emphysema, with enlargement of air spaces and destruction of lung cells (lung parenchyma), loss of lung elasticity, and closure of small airways. In another approach, chronic obstructive pulmonary disease can be considered a chronic lung airway obstruction syndrome associated with any or all of the following: chronic bronchitis, emphysema, asthma.
This is a serious condition afflicting an estimated 14 million people in the US alone. In the US, airflow obstruction has been found in approximately 14 percent of white male smokers, as compared with approximately 3 percent of white male nonsmokers. Chronic obstructive pulmonary disease is now the 4th leading cause of death in the US, and it is the only common cause of death that is increasing in incidence.
The increase in incidence is also occurring worldwide: the World Health Organization predicts that by 2020 chronic obstructive pulmonary disease will rise from its current ranking as the 12th most prevalent disease worldwide to the 5th, and from the 6th most common cause of death to the 3rd. Reasons for the dramatic increase in worldwide incidence evidently include reduced mortality from other causes, such as cardiovascular disease in industrialized countries and infectious diseases in developing countries. But a marked increase in cigarette smoking and environmental pollution in developing countries is apparently also contributing to the increased incidence.
The following points are made by Peter J. Barnes (New England J. Med. 2000 343:269):
1) In general, the mechanisms of airflow limitation in chronic obstructive pulmonary disease are as follows: In the peripheral airways of patients with this disease, as compared with normal peripheral airways, there is airflow limitation due to a variable mixture of a) loss of *alveolar mechanisms; b) *inflammatory obstruction of the airway; and c) luminal obstruction with mucus.
2) Molecular genetics: Long-term monitoring of lung function reveals that progressive and substantial airflow obstruction occurs in only a minority of cigarette smokers (15 percent of whites and 5 percent of Asians), and this strongly suggests that genetic factors may determine in which smokers airway limitation will develop. Further evidence that genetic factors are important comes from the familial clustering of patients with early-onset chronic obstructive pulmonary disease and from the differences in the prevalence of the disease among racial groups. There are certain genetic anomalies: The reported risk of chronic obstructive pulmonary disease is 10 times the normal level in a Taiwanese population with a certain specific *polymorphism (a polymorphism in the promotor region of the gene for *tumor necrosis factor alpha). However, members of a British population with the same polymorphism do not have an increased risk of the disease.
3) Risk factors: In industrialized countries, cigarette smoking accounts for most cases of chronic obstructive pulmonary disease, but in developing countries other environmental pollutants, such as particulates associated with cooking in confined spaces, are important causes. It is likely that there are important interactions between environmental factors and a genetic predisposition to the disease. Air pollution (particularly with sulfur dioxide and particulates), exposure to certain occupational chemicals (e.g., cadmium), and passive smoking may all be risk factors.
4) Inflammation: It is now apparent that there is a chronic inflammatory process in chronic obstructive pulmonary disease, but it differs markedly from that seen in asthma, with different inflammatory cells, mediators, inflammatory effects, and responses to treatment. Histopathological studies indicate that most inflammation in chronic obstructive pulmonary disease occurs in the peripheral airways (bronchioles) and lung parenchyma. The bronchioles are obstructed by *fibrosis and infiltration with *macrophages and *T lymphocytes: lung parenchyma is destroyed and the number of macrophages and T lymphocytes is increased.
5) The author concludes: "In view of the high and increasing global prevalence of chronic obstructive pulmonary disease, its continuing high *morbidity and mortality, and the consequent high health care costs, more attention should be focused on the prevention and treatment of the disease... [This disease] remains insufficiently recognized in family practice and is often still treated as poorly responsive asthma. Smoking cessation is of the utmost importance, but chronic obstructive pulmonary disease may also be due to other causes. Why only some people are susceptible to [the disease] is not yet understood, but it is likely that advances in molecular genetics will provide the means to identify those at risk in the future. At present, smoking cessation is the only strategy that prevents the relentless progression of airflow obstruction..."
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
alveolar mechanisms: A "bronchus" is one of the two subdivisions of the trachea that serve as airways to and from the lungs, and a "bronchiole" is one of the approximately 6 generations of linear branches of the bronchi. In general, an "alveolus" is a small cavity or socket, and in this context, a [pulmonary] alveolus is one of the thin-walled sac-like terminal dilations of the respiratory bronchioles and alveolar ducts across which gas exchange occurs between alveolar air and the pulmonary capillaries.
inflammatory obstruction: In general, an "inflammatory change" is a response of tissues to irritation or injury. The response involves a dynamic complex of cellular and chemical reactions that occur in the affected blood vessels and adjacent tissues.
polymorphism: A genetic polymorphism is a naturally occurring variation in the normal nucleotide sequence of the genome within individuals in a population. Variations are denoted as polymorphisms only if they cannot be accounted for by recurrent mutation and occur with a frequency of at least about 1 percent.
tumor necrosis factor alpha: A *cytokine produced by various types of cells, mediating the expression of a variety of genes, and capable of causing *cytolysis of certain tumor cell lines.
cytokine: A cytokine is any substance that promotes cell growth and cell division. Certain cytokines are endogenous, and need to be controlled by cell regulatory mechanisms. When these mechanisms fail, endogenous cytokines may be implicated in serious human diseases such as rheumatoid arthritis, where apparently deregulated cytokines cause the inflammatory response that produces the symptoms. As a promoter of cell growth and division, a cytokine acts as a messenger to cells, and the transmission of the message requires a binding of the cytokine molecule to a cytokine-specific receptor on the cell surface. This receptor is either a protein or a protein complex or a part of a protein.
cytolysis: In general, the breakdown of cells, especially by destruction of their outer membranes.
fibrosis: In general, the formation of fibrous tissue as a reparative or reactive process (e.g., scarring).
macrophages: Amoeba-like white blood cells (leukocytes) that are able to surround and digest foreign entities such as bacteria and protozoa.
T lymphocytes: (T-cells) Lymphocytes (lymph cells, lympho-leukocytes) are a type of leukocyte (white blood cell) involved in the immune response. There are two classes of such lymphocytes: 1) the B-cells, which after a cascade of immune system events involving a specific antigen change into proliferating specific antibody producing plasma cells; 2) the T-cells, one subclass of which (cytotoxic T-cells) interacts directly with foreign invaders such as bacteria and viruses, while the other subclass of T-cells (helper T-cells) is involved in the proliferation of antibody-specific B-cells.
morbidity: In general, in medicine, this refers to a diseased state; in particular, the term refers to the ratio of the diseased to the well in a community.
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