Study of pulmonary function tests in patients of diabetes mellitus (NIDDM) with chronic obstructive pulmonary disease or asthma

Content

1. INTRODUCTION

2. AIMS AND OBJECTIVES

3. REVIEW OF LITERATURE

4. MATERIAL AND METHODS

5. RESULTS

6. DISCUSSION

7. SUMMARY AND CONCLUSION

8. BIBLIOGRAPHY

9. ANNEXURES

KEY TO MASTERSHEET

ABBREVIATIONS

Introduction

Diabetes is a systemic disease. The presence of an extensive pulmonary microvascular circulation and abundant connective tissue raises the possibility that lung may be a target organ of the pathologic process induced by chronic hyperglycemia.

Twenty years from now it is envisaged that there will be a worldwide incidence of more than 330 million diabetic patients and majority of whom will be afflicted with type 2 diabetes[1]. Prevalence of diabetes in adults worldwide was estimated to be 4% in 1995 and to rise to 5.4% in 2025[2]. The major part of this numerical will occur in developing countries. There will be a 42% increase, in the developed countries and 170% increase, in the developing countries. Thus, by the year 2025, > 75% of people with diabetes will reside in developing countries, as compared with 62% in 1995. The countries with the largest number of people with diabetes are, and will be in the year 2025, India, China and the U.S. In developing countries, the majority of people with diabetes are in the age range of 45-64 years[2]. A recent meta analysis of epidemiological studies on diabetes in India revealed prevalence rate of Diabetes in India among adults in both urban and rural population to be 62..47 per thousand[3].

The interest in the relationship between diabetes and obstructive lung diseases has been pursued only recently [4-7]. The prevalence of asthma is significantly higher in patients with type II diabetes mellitus (DM), independent of other comorbid conditions[4]. Chronic obstructive pulmonary disease (COPD) may be a risk factor for developing type 2 diabetes[5]. Also hyperglycemia is associated with adverse clinical outcomes in patients with acute exacerbations of COPD[6]. The exploitation of the potential for interventions that improve mortality and even reverse the course of the disease in COPD will require a better understanding of the relationship of COPD to novel risk factors, such as hyperglycemia and diabetes[7].

Another aspect to this relationship between diabetes and obstructive lung diseases is the applicability of newer and novel therapeutic approaches in this subgroup of patients. The effect of inhaled insulin in subjects with diabetes and chronic lung disease, such as asthma or COPD, is of particular interest because these diseases are quite common, and it is likely that patients with asthma or COPD who are poorly controlled on oral agents and are reluctant to start subcutaneous insulin would benefit from inhaled insulin to improve their glucose control[8].

Also several prospective studies have found that impaired pulmonary function may increase the risk for developing diabetes[9].

With this background, this study was undertaken to determine the pulmonary function parameters in patients of diabetes mellitus (NIDDM) with COPD or asthma.

Aims & Objectives

1. To evaluate the status of pulmonary functions ( pulmonary function tests - spirometry with reversibility, DLCO, lung volumes including total lung capacity, residual volume, residual volume / total lung capacity) in diabetics (NIDDM) with COPD or asthma.
2. To correlate the pulmonary functions (DLCO and lung volumes) with severity of airflow limitation in diabetics (NIDDM) with COPD or asthma.
3. To correlate FVC% with duration of diabetes in diabetics (NIDDM) with COPD or asthma.
4. To correlate the severity of airflow limitation with the glycemic control, duration of diabetes and duration of respiratory symptoms in diabetics (NIDDM) with COPD or asthma.
5. To determine the health related quality of life impairment in diabetics (NIDDM) with COPD or asthma and correlate it with severity of airflow limitation.

Review of Literature

HISTORY OF DIABETES:

Diabetes: ‘dia’ = through - ‘betes’ = to go

Diabetes mellitus has been described in literature more than 2000 years ago. In 1552 BCE Egyptian physician Hesy-Ra of the 3rd dynasty made the first known mention of diabetes - found on the Ebers Papyrus - and listed remedies to combat the 'passing of too much urine’.

Charaka and Susruta (600 - 400 BC) named it ‘Madhumeha’ in ‘Susruta Samhita’ meaning rain of honey.

The following masterly description of severe diabetes by Arateus from about A.D. 150 represents the sum of our knowledge up until the second half of the 17th century[10]: “Diabetes is a wonderful affection, not very frequent among men, being a melting down of the flesh and limbs into urine. Its course is of a cold and humid nature, as in dropsy. The course is the common one, namely, the kidneys and the bladder; for the patients never stop making water, but the flow is incessant, as if from the opening of aqueducts. The nature of the disease then, is chronic, and it takes a long period to form: but the patient is short-lived, if the constitution of the disease be completely established; for the melting is rapid, the death speedy.”

In 1674, Thomas Willis, a physician, an anatomist, and a professor of natural philosophy at Oxford, discovered (by tasting) that the urine of individuals with diabetes was sweet[11]. This was actually a rediscovery, for unbeknownst to him; an ancient Hindu document by Susruta in India in about 400 B.C. had described the diabetic syndrome as characterized by a”honeyed urine”. It was Matthew Dobson of Manchester, England, who demonstrated, in 1776, that persons with diabetes actually excrete sugar in the urine.

Banting and Best came up with the most dramatic discovery of 20th century in 1921 and Insulin which was named so by Jean de Meyer, was made available to treat Diabetes. The awarding of the Nobel Prize in Medicine in October 1923, 18 months after the first news of the discovery of insulin perhaps delineated how important this discovery was.

In comparison to the disease itself, the description of its complications is relatively new. The first description of retinopathy was recorded just over 120 years ago by Nettleship in UK. Kimmelsteil and Wilson described lesions of nephropathy less than 70 years ago. Neuropathy has to its credit, an older description by Rollo in 1798 who had postulated that diabetes was a result of nervous system disease. Marchal de Calvi in 1864 was the first to suggest that neuropathy was caused by diabetes rather than the reverse.

Lung dysfunction in diabetes mellitus has been investigated over past three to four decades only.

HISTORY OF COPD AND ASTHMA:

The evolution of knowledge concerning COPD and its components covers 200 years.

Some of the earliest references to the description of emphysema include: Bonet’s description of voluminous lungs in 1679; Morgagni’s (1769) description of 19 cases in which the lungs were “turgid” particularly from air and Baille’s illustration of the emphysematous lung, thought to be that of Samuel Johnson (Baille 1789, Bishop 1959).

The beginning of our clinical understanding of chronic bronchitis component of copd can be traced to Badham (1814) who used the word catarrh to the chronic cough and mucus hypersecretion that are cardinal symptoms.

In 1819 Laennec invented the stethoscope, which became the first instrument by which lung structure and functions could be indirectly studied. In 1821 Laennec first described the symptoms and physical signs of emphysema in hi treatise of diseases of the chest.

In 1846 Hutchinson invented the spirometer. Today, this instrument is the key to diagnosing COPD in all of its stages and to assessing responses to therapy. In 1944 Christie suggested that, “the diagnosis should only be considered certain when dyspnea on exertion, of insidious onset, not due to bronchospasm, or left ventricular failure, appears in a patient who has some of the physical signs of emphysema together with chronic bronchitis or asthma”.

Charles Fletcher devoted his life to the study of natural history of COPD. He recognized the risks of smoking and the accelerated rate of decline of FEV1 in susceptible smokers on the pathway to disabling symptoms.

At the close of the 1950s and in the early 1960s, several international meetings addressed uncertainties in the nomenclature of COPD: one by the Ciba Foundation, another by the American Thoracic Society, and the third by the British Medical Research Council. All three arrived at virtually the same conclusion: the essential features of so-called chronic bronchitis in England and of emphysema in the United States are the same. In 1966, the differences in nomenclature between the British and American terminology were reconciled, and Briscoe's suggestion that chronic bronchitis, asthmatic bronchitis, and emphysema be included under the rubric "chronic obstructive pulmonary disease" was widely adopted[12].

Although asthma has been described as a medical entity since the time of Aretaeus, the Cappadocian, in approximately 100 A.D.[13], the constellation of physical findings and signs that we currently recognize as asthma dates from the work of John Floyer[14] in 1698. By 1900, it was well established that certain forms of asthma could be brought on by exposure to environmental allergens.

Since then we have covered a great distance in our understanding of COPD and asthma.

Our current understanding of these diseases can be summarised in their present definitions.

Based on current knowledge, a working definition of COPD has been provided by Global Initiative for Chronic Obstructive Lung Disease (GOLD).

“Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.”[15]

Based on the functional consequences of airway inflammation, an operational description of asthma has been provided by Global Initiative for Asthma (GINA) guidelines. “Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment.”[16]

HISTORY OF PULMONARY FUNCTION TESTS:

The volume of air which a man can inhale during a single deep breath was first measured by Borelli (1679). The need for temperature correction was pointed out by Goodwyn (1788). In 1848, Hutchison defined vital capacity as greatest voluntary expiration following deepest inspiration possible and designed a spirometer for its estimation. He also suggested that vital capacity varied with age, sex and height.

Gas dilution method was first used by Humphrey Davy in 1700 to measure the residual volume. The role of elastic recoil of lung in causing expiration was demonstrated by Danders (1849). Peabody in 1915 first attempted to correlate vital capacity to breathlessness. He also compared the ventilation during inhalation of carbon dioxide and that during exercise.

Strohl in 1919 advocated the use of forced capacity in clinical testing. The role of change in lung distensibility in causing breathlessness was explored by Christie (1939). The maximum voluntary ventilation was introduced as a dynamic test of lung function by Jansen (1932).

The use of proportion of vital capacity which could be exhaled in one second (FEV1) as a guide to airway obstruction was introduced by Pinelli and Tiffeneau (1947). This method was improved and popularized in America by Gaensler (1950-51).

Marie Krogh, in 1914, first measured the diffusion capacity of lung using carbon monoxide. Refinements in the carbon monoxide method by Roughton and others extended its clinical applicability. Oglivie et al., in 1957, first introduced single breath technique for measuring DLCO.

In 1868 Bert P. introduced the total body plethysmography. He did intense experiments with animals in a closed plethysmographic system. Almost a century later, in 1969 DuBois A.B. and van de Woestijne K.P. presented the whole body plethysmograph on humans.[17]

PULMONARY FUNCTION IN DIABETES MELLITUS:

Reduction in various pulmonary function parameters has been reported in patients with diabetes over the past three decades, and many reports have plausible pathophysiological mechanisms.

Scuyler et al.[18] investigated pulmonary function in 11 young (21-28 years old) patients with type 1 diabetes and age-matched normal control subjects. This classic study was the first to report measurements of nearly all the available tests of lung function including lung elasticity, capacity to transfer carbon monoxide (DLCO, a surrogate for oxygen transfer capacity), absolute thoracic gas volumes, airflow resistance and maximal forced spirometric pulmonary function tests (PFTs). As their subjects were lifelong nonsmokers without allergies or lung disease, their finding that lung elastic recoil was decreased in these young patients with diabetes was interpreted to reflect effects of diabetes on lung elastic proteins. This was the first suggestion in the literature that the lung may be a target organ in diabetes. Because the elastic structure of the lung supports the intrathoracic airways and helps to maintain their patency, the authors suggested that patients with diabetes were at risk for developing chronic airflow obstruction. While small changes in lung elastic recoil do not have direct clinical implications, subsequent development of chronic airflow obstruction could incur significant disability due to mechanical dysfunction of the lungs and airways.

Sandler et al.[19] in their study, attempted to establish the prevalence and nature of pulmonary dysfunction in a cross section of a diabetic population and the relationship of pulmonary dysfunction to diabetic factors and complications. Forty insulin-dependent diabetic patients, 15 to 60 yr. of age, and forty healthy reference subjects matched for age, sex and race were studied. All subjects were lifelong nonsmokers and had no clinical evidence of past or present respiratory disease. Lung function was assessed from the flow-volume curve, singlebreath nitrogen washout, static lung elastic recoil and pulmonary diffusion capacity (DLCO/VA) and its components: membrane diffusing capacity (Dm/VA) and pulmonary capillary blood volume (Qc/VA). They did find decreased lung elasticity. In addition, they found decreased CO transfer capacity with decreased pulmonary capillary blood volume. Lung CO transfer capacity is significantly affected by the integrity of lung capillary endothelium and therefore the findings of Sandler et al. focused attention on pulmonary vascular changes.

The concept of the lung as a target organ for diabetic microangiopathy received continuing attention. Reports of lung function tests in patients with diabetes over the next 15 years have focused largely on pulmonary microangiopathy. Lung function tests relating specifically to pulmonary microangiopathy include CO transfer capacity and pulmonary capillary blood volume. In patients with type 1 diabetes, decreased lung transfer capacity for CO has been documented in association with evidence of other diabetic microangiopathy [8-10].

Strojek et al. [20] have investigated the influence of diabetes mellitus including the presence of late complications of the pulmonary system. To check this relationship 31 Type 1 (insulin-dependent) diabetic patients (mean age 30.6 +/- 5.32 years, mean duration of diabetes 12.9 +/- 5.05 years) were admitted into the trial and compared with 18 control subjects. Pulmonary function tests were measured including spirometric parameters, diffusing capacity, specific diffusing capacity and dynamic compliance. No disturbance of the spirometric parameters was observed in the diabetic patients. Diffusing capacity in the diabetic patients with complications was significantly lower than in both the diabetic patients without complications and the control group (81.2 +/- 16.2%, 104 +/- 13.7%, 99.3 +/- 2.8%; p < 0.001, p < 0.005 respectively). Specific diffusing capacity was significantly lower in the diabetic patients than in the control subjects (80.3 +/- 13.1% vs. 89.4 +/- 12.9%; p < 0.05).

Innocenti et al.[21] compared 23 non-smoking patients who had IDDM with 24 non- smoking healthy control subjects strictly matched for sex, age, and body mass index. Compared with controls, diabetic patients had a reduced forced vital capacity (FVC) (87.5 +/- 13.1% vs.

96.4 +/- 13.6% of the predicted; p = 0.03) and forced expiratory volume in 1 s (FEV1) (90.5 +/- 17.7% vs. 101.2 +/- 13.2% of the predicted; p = 0.02). Rosenecker et al.,[22] reported that in patients with diabetes, FVC and FEV1 declined significantly over the five year study period whereas patients without diabetes did not show a significant decline during the study period.

Yeh et al.[23] in their study on atherosclerosis risk in communities showed that at baseline, adults with diabetes had significantly lower predicted FVC (96 vs. 103%, p < 0.001) and predicted FEV1 (92 vs. 96%, p < 0.001) than those without diabetes. In prospective analyses, FVC declined faster in diabetic adults than in their non diabetic counterparts (64 vs. 58 ml/year, P = 0.01).

Boulbou et al.[24] assessed the nature of pulmonary dysfunction in type 1 diabetes and the relationship of pulmonary function tests to diabetic factors and complication. Sixteen type 1 diabetic patients and 26 control subjects matched for age and sex were studied. They performed spirometry measurements and measured pulmonary diffusing capacity (DLCO) in sitting and supine position by the single-breath method corrected by alveolar volume (VA). Glycosylated hemoglobin (HbA1c), retinopathy and microalbuminuria were included as parameters of metabolic control and diabetic complications. Diabetic patients showed a significant reduction of the following pulmonary function tests (% predicted value) as compared with control subjects: total lung capacity (TLC, 92.6 +/- 14.5 vs. 113.9 +/- 17.5, p < 0.001), lung diffusing capacity in sitting position (DLCO, 90.4 +/- 21.1 vs. 107.7 +/- 15.6, p = 0.004), lung diffusing capacity in supine position (DLCO, 88.3 +/- 19.3 vs. 111.9 +/- 19.9, p = 0.001). The differences in diffusing capacity corrected by alveolar volume in sitting and supine position (DLCO/VA) were not significant. By changing the posture from sitting to supine position both diabetic patients and control subjects significantly increased DLCO/VA (103.4 +/- 17.7 vs. 112.7 +/- 22.3, p = 0.046 and 99.5 +/- 13.4 vs. 114.4 +/- 13, p < 0.001, respectively). There was no correlation between pulmonary function tests and diabetic complications.

Maccioni et al. [25] studied the effect of insulin-dependent diabetes mellitus on pulmonary function in 22 diabetic nonsmokers (11 men) with a mean age of 40 yr (SE, 4 yr) and no history of cardiorespiratory disease. In the diabetic subjects, mean values for total lung capacity, functional residual capacity, VC, and FEV1 were similar to predicted values. Diffusing capacity did not differ significantly from corresponding values in healthy subjects. The findings show that insulin-dependent diabetes mellitus does not affect pulmonary function.

Fuso et al.[26] reported subtle pulmonary capillary blood volume abnormalities in patients with type 1 diabetes using tests of CO transfer capacity and capillary blood volume in both the seated and supine positions. Patients with normal CO transfer capacity in the seated posture showed decreased capillary volume in the supine posture relative to normal control subjects. The authors suggested seated and supine measures of control of CO transfer capacity to diagnose early pulmonary vascular damage in diabetes. Accordingly Ozmen et al.[27] noted that their failure to show a relationship between CO transfer capacity and microalbuminuria, diabetes duration or glycemic control was most likely due to relative insensitivity of the usual clinical method of measuring CO transfer capacity.

Asanuma et al.[28] analyzed pulmonary functions in 50 diabetics (31 males and 19 females) without overt lung disease, compared to 21 healthy male subjects of the same age (around 50 years old). Forced vital capacity and timed vital capacity were lower in diabetics (p < 0.005). Diffusing capacity was also decreased in male diabetics (p < 0.05). Diabetic patients showed abnormal lung function in the peripheral airways which increased with age and gas transfer was also affected by diabetic microangiopathy as well as the duration of diabetes. These changes seemed to deteriorate progressively, possibly combining and contributing to respiratory insufficiency in critical pathological conditions.

Davis et al.,[29] determined the association between diabetes mellitus and reduced lung function and reported that the forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), vital capacity (VC) and peak expiratory flow (PEF) when expressed as a percentage of those predicted (% predicted) for age, sex and height, the means of all spirometric measures were reduced by > or = 9.5%. Additionally, diabetes duration was significantly associated with FEV1 (% predicted) and PEF (% predicted) (p < or = 0.04) and had borderline associations with FVC (% predicted) and VC (% predicted) (p < or = 0.064).

Mori et al.[30] performed pulmonary function tests including assessment of the diffusing capacity (% DLCO) in 80 patients with non-insulin-dependent diabetes mellitus (45 males and 35 females) without overt lung or heart disease. The mean age of the subjects was 57.9 years and the mean duration of diabetes was 10.8 years. The % DLCO decreased significantly as the duration of diabetes increased (r = -0.38, p < 0.01), and the same relationship was also observed in non-smoking subjects (n = 37). Other pulmonary function tests (% VC, FEV1, PaO2 and PaCO2) showed no relationship to the duration of diabetes, the degree of microangiopathy or the type of treatment.

Isotani et al.[31] investigated the independent change in pulmonary diffusing capacity (DLCO) as one manifestation of pulmonary microangiopathy and analyzed the correlation between DLCO and serum ACE. They examined the association between DLCO and the ACE genes. They examined pulmonary functions, especially %DLCO/VA (DLCO corrected by alveolar volume, percent predicted) in 54 NIDDM patients and 34 age-matched normal control subjects. There was a significant reduction of %DLCO/VA (percent predicted) (p < 0.05) in diabetic patients. %DLCO/VA was negatively correlated with serum ACE values (r = 0.49, P < 0.0002, y = -1.4x + 109.3).

Guvener et al.[32] compared the capacity of gas exchange in patients with type 2 diabetes mellitus (DM) and healthy controls and also investigated the effects of various factors on alveolar capillary permeability. A total of 37 subjects, 25 patients with DM and 12 healthy controls were recruited for the study. All the participants were evaluated with simple spirometric tests and single breath carbon monoxide (CO) diffusion test (DLCO). The ratio of DLCO value to the alveolar ventilation (VA) was used to assess alveolar membrane permeability. The results of simple spirometric tests which determined lung capacity were similar in the diabetic patients and the healthy controls. Ratio of DLCO/VA, which determines alveolar membrane permeability, revealed statistically significant decline in pulmonary gas exchange in the diabetic group (p= 0.037). This study demonstrated the decreased alveolar gas exchange capacity in diabetic patients compared with healthy controls.

The pathophysiological mechanism for reduction of DLCO in diabetes mellitus was attributed to pulmonary microangiopathy [33-38].

Sandler et al.[33] concluded that lung should be considered a target organ in diabetes, and noted that the histopathologic evidence of lung involvement in subjects with diabetes mellitus has included thickened alveolar epithelial and pulmonary capillary basal laminae, the latter being suggestive of existing pulmonary microangiopathy.

Abnormal pulmonary function has been detected in some diabetic patients; the most consistent abnormalities are reduced lung volumes in young (aged less than 25 years) insulin- dependent diabetic subjects, reduced pulmonary elastic recoil in both young and adult (aged greater than 25 years) diabetic subjects, and impaired diffusion due to a reduced pulmonary capillary blood volume in the adult group. Nonenzymatic glycosylation-induced alteration of lung connective tissue is the most likely pathogenic mechanism underlying mechanical pulmonary dysfunction in diabetic subjects, while the most tenable explanation for impaired pulmonary microangiopathy in these patients is the presence of underlying pulmonary microangiopathy. The finding of abnormal lung function in some diabetic subjects suggests that the lung should be considered a "target organ" in diabetes mellitus; however, the clinical implications of these findings in terms of respiratory disease are at present unknown[33].

Matsubara et al.[34] examined and compared the pulmonary function and microscopic change of the lungs of diabetic patients with those of non-diabetic patients to assess the diabetic microangiopathy in lung. For pulmonary function study, spirogram flow-volume curve, diffusing capacity and arterial blood gas analysis were performed in 52 diabetic patients and 48 age and sex-matched control subjects. Diffusing capacity, % vital capacity, total lung capacity, residual volume and 25% maximal expiratory flow were significantly less in the diabetic group than in the control group. For histopathological study, the lungs of 35 autopsied cases of a diabetic group and 26 autopsied cases of a non-diabetic group were examined. The two groups were compared and studied by measuring the thickness of alveolar capillary walls, pulmonary arteriolar walls and alveolar walls with a light microscope and an eye piece micrometer. The alveolar capillary walls, the pulmonary arteriolar walls and the alveolar walls had thickened significantly in the diabetic patients. These studies suggested that histological changes (microangiopathy) in the lungs are a cause of pulmonary function abnormalities.

Vracko et al.[35] stated that epithelial and capillary basal laminae (BL) of alveoli are significantly thicker in diabetics than they are in age-matched control subjects. The degree of thickening does not correlate significantly with patient age or with known duration of diabetes. The thickness of both types of BL in the lungs correlates significantly with thickness of BL in renal tubules and muscle capillaries. However, in muscle capillaries and in renal tubules, the BL deposits are 5 to 10 times greater than they are in the lungs. The effects of BL changes on pulmonary function remain to be explored.

In their review, Ardigo et al.[37] showed that insulin deficiency induces an increase in blood glucose levels that, the diabetic disease seems to hit the pulmonary microcirculation as any other organ by increasing vessel wall thickness and impairing gas exchange, which leads to a measurable loss of function and respiratory efficiency. In addition, a diabetic lung is more susceptible to low respiratory tract infections by atypical microorganisms and more likely to host severe episodes of pneumonia than a normal, non-diabetic lung.

Structural modifications of the lung parenchyma were observed by Nicolaie et al.[38] such as the narrowing of the alveolar space, the flattening of the alveolar epithelium and the expansion of the interstitium. Aside from the involvement of the pulmonary vessels there is the involvement of the basement membranes of the alveolar epithelium, the bronchial epithelium and the pulmonary capillaries. The consequences of local oxidative stress, the increased vascular permeability and the modifications in mucus secretion lead to the reduction of pulmonary volumes, pulmonary diffusion capacity, and elastic recoil with involvement of restrictive lung disorders, diminished bronchial reactivity and diminished bronchodilation.

PULMONARY FUNCTION IN COPD AND ASTHMA:

SPIROMETRY:

The hallmark of chronic obstructive pulmonary disease (COPD) is airflow obstruction. This is identified by pulmonary function testing and thereby used for the diagnosis of COPD and staging of disease severity. SpirometrREVIEW OF LITERATUREy is essential for diagnosis and provides a useful description of the severity of pathological changes in COPD. For this purpose reduction in the post bronchodilator ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) < 0.7 is recommended to define airflow limitation in COPD patients. Spirometry should be performed after the administration of an adequate dose of an inhaled bronchodilator (e.g.400 micrograms salbutamol) in order to minimize variability. Thus post-bronchodilator FEV1/FVC and FEV1 measurements have been recommended for the diagnosis and assessment of severity of COPD[15]

Both asthma and COPD are defined by decreases in the FEV1/FVC ratio. FEV1 in asthma patients is considered to be at least partially (12% change in FEV1) or completely reversible and to vary significantly throughout the day[39]. COPD, by definition, is never completely reversible, and significant reversibility often leads to exclusion from clinical trials.

Both chemically induced and exercise-induced hyperresponsiveness are defining characteristics of asthma but are not traditionally associated with COPD[40].

The degree of reversibility in FEV1 which indicates a diagnosis of asthma is generally accepted as ≥ 12% and ≥ 200 ml from the pre-bronchodilator value[41].

The acute improvement in expiratory flow rates, such as FEV1 following bronchodilator use, is on average greater in asthma patients than in COPD patients (16% vs. 11%, respectively). However, despite the common use of bronchodilator reversibility in the clinical and research setting to distinguish asthma from COPD, the diagnostic effectiveness of this parameter is poor in unselected patients [42, 43].

Mannino et al. in one large study,[44] using a threshold bronchodilator FEV1 change of 15%, determined only a 44% sensitivity for detecting asthma and a 72% specificity in distinguishing asthma from COPD. Kesten et al. showed that increasing the minimum FEV1 threshold change to 20% increased the specificity to 84% but dramatically decreased the sensitivity[43]. Further Mannino et al in their large population-based analysis[44] found that 30% of individuals with fixed airflow obstruction have a history of asthma.

The traditional view of asthma as a "reversible" disease and COPD as being "irreversible" is no longer tenable. COPD is now defined as airflow limitation that is "partially reversible"[45, 46] and this reversibility is generally greater with anticholinergic therapy [47-49]. Furthermore, asthma probably becomes less reversible with chronicity and poor control that lead to airway remodeling[50].

DLCO:

Diffusing capacity is a measurement of carbon monoxide (CO) transfer from inspired gas to pulmonary capillary blood[51].

Since small airways and perhaps also parenchymal abnormalities are associated with asthma, it is not surprising that significant gas exchange abnormalities occur in asthma. The DLCO is an indirect measure of the ability of the lungs to exchange gas at the alveolar-capillary interface. Thus DLCO probably better reflects the alveolar capillary surface area. Thus in emphysema DLCO is typically reduced and in asthma it is usually normal or somewhat increased [52-54].

Collard et al.[54] studied single breath diffusing capacity for carbon monoxide in 80 consecutive never-smoker patients with uncomplicated stable asthma. The mean (SD) value of DLCO was increased to 117 (17) percent of predicted values; individual values were either within or above normal limits; diffusion was also elevated at 116 (19) percent after correction for alveolar volume (transfer coefficient, DLCO/VA). The DLCO was not correlated with atopic status, duration of asthma, or results of spirometric tests; there was a weak negative correlation between DLCO/VA and FEV1 or residual volume.

Roger S.[55] performed a study to test the hypothesis that carbon monoxide diffusing capacity (DLCO) is elevated in asthmatic patients with minimal airflow limitation and/or hyperinflation. In ten asthmatic and ten healthy subjects, DLCO and its components, membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Qc) were measured by the single breath method. Values were normalized for alveolar volume (VA). The mean DLCO/VA was higher in the asthma groups as was the Qc/VA. He concluded that DLCO/VA might be increased in asthmatic patients with only mild airflow limitation; this might be due to an elevated capillary blood volume.

In asthma, factors that may increase DLCO include increased numbers of red blood cells and hemoglobin within the thorax, either within the pulmonary vasculature or possibly the alveolar space itself, as well as an increased gradient of blood flow to the upper lung zones, where higher ratios of ventilation to perfusion increase the effective pressure gradient for carbon monoxide[52].

The DLCO is typically decreased in COPD and increased in asthma[56].Also as alveolar volume (VA) increases, the DLCO also increases. Therefore, when lung volumes are abnormal (as is often the case with both asthma and COPD) the DLCO should be corrected for lung volume, which is usually expressed as the DLCO/VA [57, 58].

In COPD patients, the DLCO values are typically decreased. The decreases are thought to be directly related to the loss of alveolar-capillary surface area that is associated with emphysema[59].

Brashier et al.[60] investigated the association between spirometric indices and DLCO in patients with COPD. 35 COPD subjects of variable severity (grade I - n=3, grade II - n=13, grade III - n=10 and grade IV - n=7) were recruited in this study. A significant positive correlation was observed between FEV1, FVC, FEF25-75 (all % predicted), FEV1/FVC and DLCO% predicted (R2 =0.67, p= 0.000; R2 =0.59, p= 0.000; R2 =0.635, p= 0.000; R2 =0.556, p= 0.000, respectively) FEV1 % predicted correlated best with DLCO% (DLCO% predicted = 30.7 + 0.78 FEV1% predicted).They concluded that FEV1, FVC, FEF25-75% and FEV1/FVC correlate positively with DLCO values in patients with COPD.

Jessica et al[61] in their study on 38 COPD patients with FEV1<50% demonstrated a positive correlation between baseline DLCO and post bronchodilation. The coefficient of correlation between FEV1 and DLCO increased significantly after bronchodilation.

Bozkurt et al.[62] in their study on 30 stable COPD patients determined a significant correlation between FEV1 and DLCO (p < 0.004) and a negative correlation was also determined between FEV1 and RV (p < 0.09). In their study mean FEV1 was 1.2 L (43.3%), FEV1/FVC was 58.0% (min.32-max 78), RV was 3.9L (182%), TLC was 6.0 L (100%), DLCO was 6.3 mmol/kPa.sn (76.1%), and DLCO/VA 1.5 (0.51-2.69).

LUNG VOLUMES:

Static lung volume tests are often routinely assessed along with spirometry for patients with various chronic obstructive airway diseases. Two common reasons for assessing the lung volumes are (1) to determine the presence or degree of lung hyperinflation, and (2) to look for a superimposed restrictive lung disorder. Static lung volumes include the total lung capacity (TLC), the residual volume (RV), and the functional residual capacity (FRC). The definition of airways obstruction has been standardized as an abnormally low FEV1/FVC ratio and a low FEV1 % predicted. However, the definition of the term "lung hyperinflation" is currently imprecise and is variously based on posteroanterior and lateral chest radiograph patterns, the FRC % predicted, the RV/TLC ratio, the RV % predicted, or the TLC % predicted [63,64].

Dykstra et al.[64] studied to determine the correlates of static lung volumes in patients with airways obstruction, and also if static lung volumes differed between asthma and COPD. They examined the data from all of the adult patients (mean age of 69) who were referred to a pulmonary function laboratory from January 1990 through July 1994 with an FEV1/FVC ratio of < 0.70 and tested using a body plethysmograph. Of the 4,774 patients observed with evidence of airways obstruction, 61% were men. Self-reported diagnoses included asthma, 19%; emphysema or COPD, 23%; chronic bronchitis, 1.5%; and alpha1-antiprotease deficiency, 0.6%. Fifty-six percent of the patients did not report a respiratory disease. The degree of hyperinflation, as determined by the residual volume (RV)/total lung capacity (TLC) ratio, or the RV % predicted (but not the TLC % predicted), was strongly associated with the degree of airways obstruction (the FEV1 % predicted). Patients with moderate to severe airways obstruction and high RV and TLC levels were found more likely to have COPD than asthma. For patients with moderate to severe airways obstruction (an FEV1 of < 53% of predicted), the mean RV was higher in patients with COPD only (an RV of usually > 200% of predicted and up to 350% of predicted) when compared to patients with asthma only. Of the total of 4,774 patients, 1,872 patients (39.2%) had a reduced VC. Of these patients, 1,634 patients (87.3%) had a high RV/TLC (above the normal range), and only 177 patients (9.5%) had a low TLC (below the lower limit of the normal range). The mean FEV1/FVC was significantly higher for patients with a low TLC when compared to the other patients, respectively: 62% vs. 51% (p < 0.001). Patients with a low TLC were also less likely than the other patients to have a severe airways obstruction (an FEV1 of < 40% of predicted), respectively: 36% vs. 52% (p < 0.001).

Sin et al.[65] investigated clinical and functional characteristics in elderly subjects who had a history of late onset asthma and compared these findings with age matched COPD patients. Fifty one patients over 60 years of age were selected for the study (27 patients with late-onset asthma, 24 patients with COPD). Pulmonary function tests including airflow rates, lung volumes, airway resistance, diffusing capacity, and arterial blood gases analysis were performed in all patients. FEV1 was lower in COPD patients than in asthmatic patients. Bronchial reversibility in asthmatics became significantly higher than in COPD patients. While FRC and RV were increased in both groups showing same degree of pulmonary hyperinflation, patients with COPD demonstrated significantly decreased DLCO when compared to asthmatic patients.

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