Biomedical subjects
Publications and source records attributed to R J Knudson.
In this review article, the effects of old age on lung structure and function are discussed. Changes in lung morphology and biochemistry are correlated with changes in lung mechanics and gas exchange, as well as with the respiratory system's adaptability to the stresses of exercise and sleep. The effects of aging on the lungs' defense mechanisms are related to pulmonary diseases of the elderly.
Family aggregation of pulmonary function measurements was analyzed in the nuclear families of the Tucson epidemiologic study of airway obstructive diseases (AOD). There were 271 parental pairs and their natural children who had satisfactory pulmonary function data. Initial regression analysis showed significant correlations of the pulmonary function variables after controlling for age and sex. Body habitus, as measured by the Ponderal Index, was highly aggregated as well. Pulmonary function measurements were aggregated in families independent of family size, reported diagnosed AOD, and children's smoking, even though both asthma and smoking showed significant familial aggregation. After controlling for the familial aggregation of body habitus, a major determinant of pulmonary function, there was no remaining independent aggregation of pulmonary function measurements. It was also determined that parental passive smoking had no effect on children's pulmonary function measurements.
We studied 143 Pi MZ heterozygous (MZ) subjects from random populations that had been examined previously for alpha 1-antitrypsin phenotype. Each Pi MZ subject was closely matched with a Pi M control subject from the same population at each of 6 centers. An expanded National Heart, Lung and Blood Institute (NHLBI) respiratory symptom questionnaire was completed by each subject. Pulmonary function tests designed to detect established as well as early obstructive airway abnormalities were administered. Multivariate analysis of the variance of data from the questionnaire and pulmonary function tests corrected for age, race, sex, and smoking history showed no significant difference (p less than 0.05) between subjects of Pi MZ and Pi M phenotype. The size of the populations studied and number of observations made for each variable were sufficient to assure that small differences could be detected with 95% power. We conclude that MZ phenotype alone carries no greater risk of developing lung disease than M phenotype.
Measurements of ventilatory function, distribution of ventilation, diffusing capacity, and lung mechanics were made on healthy middle-aged smokers and nonsmokers drawn from a randomly selected population in order to assess the effects of cigarette smoking and the interrelationships of the several indices of lung function. Although very few subjects had abnormal function, there were significant differences in most indices of function between smokers and nonsmokers. For the total group studied, there were significant correlations between various indices of function. A significant proportion of the variance in diffusing capacity and in diffusing capacity per liter of lung volume can be accounted for by an index of lung recoil which may, in turn, be related to size of terminal air spaces.
Air and helium-oxygen maximum expiratory flow-volume curves were employed in an epidemiologic field study to assess the utility of density dependence as a screening test. Of 1,584 subjects tested, only 54.1 percent were able to perform the test with vital capacities for the two gases that agreed to within 5 percent. Subjects unable to perform the test properly tended to be older, with a greater prevalence of ventilatory function abnormalities and respiratory problems, than those who could perform the test. There was poor concordance between density dependence, or lack thereof, and standard ventilatory function measurements or evidence of respiratory disease. Under field survey conditions, the test of density dependence did not appear to be a useful screening tool.
A mechanical model was employed to examine phase and amplitude relationships between simulated pleural and mouth pressures during panting at different frequencies with and without lower airway obstruction and with rigid or flaccid extrathoracic airways. Results confirm the hypothesis that, in the presence of lower airways obstruction, compliant extrathoracic airways act as a shunt impedance. Consequently, mouth pressure changes may be out of phase with and underestimate changes in pleural pressure, affecting the measurement of thoracic gas volume.
In a study of individuals of the same sex and similar age and size, between subject variability was noted in lung recoil, lung size, density dependence of maximum expiratory flow, tracheal cross-sectional area, and anatomic dead space. No significance was observed in the relationships to one another of lung size or either estimate of airway size, nor did the magnitude of the change in flow with changes in gas density show a consistent relationship to any of the size variables. The results indicate that there is a dissociation between tracheal dimensions and anatomic dead space as well as between airway size and lung size, suggesting that dysanapsis is a general phenomenon. This introduces additional sources of interindividual variability of maximum expiratory flow and measurements of density dependence of flow.
Density dependence of maximum expiratory flow was considered in terms of equal pressure point and wave speed theories of flow limitation. It appears likely that the sites of flow-limitation, patterns of flow, and airway geometry differ with the density of the gas being expired. Because the conditions which determine maximum expiratory flow for helium-oxygen and for air differ, measurement of density dependence is of questionable value as a test for peripheral airways dysfunction.
On the basis of their answers to a self-administered questionnaire, 697 nonsmoking healthy subjects were chosen from a randomly selected sample representative of the white non-Mexican-American population of Tucson, Arizona, enrolled in a longitudinal study of respiratory health. For each subject, the first satisfactory set of flow-volume data obtained during the first 3 consecutive surveys was selected for analysis. For forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), the single best value for each subject was selected. Other flow-volume measurements were derived from the single test with the best sum FEV, plus FVC. These data were used to derive improved prediction equations for each sex by age group for 5 spirometric and flow-volume variables. The resulting predicted values demonstrate the effects of development, maturation, and senescence on ventilatory function. "Normal" limits are proposed that take into consideration the between-subject variability and non-Gaussian distribution of the various measurements.
Using data obtained during the first four complete surveys of a general population sample (2,435 spirometric studies on 916 different asymptomatic nonsmoking subjects), we have derived mathematically continuous equations designed to describe the stages of growth, maturation, and subsequent decline in the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). With this type of analysis, there appears to be a period from late childhood through adolescence in which maturation significantly increases FVC and FEV1 independent of growth, and a stage from late adolescence to the early or mid-30s in which there is relatively little change in these measurements. Progressive decline in FVC and FEV1 may not actually begin until the mid-30s. The mathematical formulae presented here were derived in a manner intended to describe biologic events and are not intended for use as prediction equations. The FEV1/FVC ratio appeared to be primarily a function of the FVC itself in young subjects. After the age of 33 years, FEV1/FVC also decreased with age, independent of the size of the FVC.
The relationships of smoking, allergy skin test reactivity, and serum IgE to ventilatory function have been analyzed in 1,182 subjects from a general population sample. The study group consisted of subjects aged 35 or more who deny previous lung surgery, old tuberculosis, or a current diagnosis of heart disease in the absence of chronic bronchitis or emphysema. Impairment of the forced expiratory volume in one second (FEV1) shows a definite relationship to total serum IgE. However, this relationship is significant only for a low FEV1 which is accompanied by symptoms suggesting asthmatic or a chronic bronchitis type disease. Allergy skin test reactivity to a battery of common aeroallergens shows no overall relationship to FEV1. However, after accounting for total serum IgE, positive allergy skin tests tend to be associated with high rather than low FEV1 values. The findings suggest that some type of IgE which is not specific for aeroallergens but which is associated with smoking, may be important in the pathogenesis of the "chronic asthmatic bronchitis" syndrome.
The history of surgery for the treatment of emphysema and its complications is long and complex and, with improved understanding of the pathophysiology, most procedures have been discarded. Present clear indications for surgery are mainly large or increasing bullae that result in compression of apparently good lung tissue, and complications of bullous emphysema such as pneumothorax and infection. With localized giant bullae the results of local resection can be as dramatic as the effects of pleural drainage for tension pneumothorax. Lobectomy should not be undertaken until bullae have been removed locally and application of positive pressure has failed to reveal any expandable lung tissue--a rare situation. Resection of small bullae generally has no effect on lung function. The indications for resection of large bullae in the presence of diffuse emphysema require careful individual study. In such cases even a small increment of function may be of great clinical benefit, and there is evidence that longevity can be increased. Finally, two-stage local drainage of tension bullae may be indicated in those rare cases in which open thoracotomy cannot be considered for other reasons.
In this study of a general population sample in Tucson, Ariz., smokers showed higher levels of serum IgE despite having a lower rate of allergy skin-test reactivity to common aeroallergens than nonsmokers. The prevalence of rhinitis was closely related to the level of serum IgE in atopic subjects regardless of smoking habits. In nonatopic smokers, elevated IgE levels were not associated with high rhinitis rates. However, high IgE levels in nonatopic smokers were related to increased rates of diagnosed asthma, wheeze, and chronic cough and/or sputum (C/S). These relationships were especially striking in subjects over the age of 54. In older nonatopic smokers, reported prevalences of "chronic bronchitis" and of functional impairment also increased in relation to the level of serum IgE. Reduced ventilatory function showed this relationship to IgE only when accompanied by C/S. It is suggested that the excess IgE related to smoking is qualitatively different than that found in subjects reacting to aeroallergens, is not important in the pathogenesis of upper respiratory tract disease, but may play a role in the development of some lower respiratory tract disorders.
To examine criteria to assess significant changes of measurements derived from the forced expiratory vital capacity (FVC), and to examine changes in the peak expiratory flow (PEF) maneuvers, ten subjects were tested on approximately 30 occasions. Since mini Wright peak flow meters are increasingly used for clinical and research purposes, peak flow intraindividual variability and relations to FVC peak flow were examined, each set of tests consisting of five FVC maneuvers and one peak flow. Measurements on a pneumotachograph included FVC, (FEV1), maximum mid-expiratory flow (MMF or FEF25-75%), and instantaneous maximum expiratory flow after 50 and 75 percent expiration of the FVC. PEF measurements were derived using the mini Wright peak flow meter and the pneumotachograph. The coefficients of variation for the FVC measurements were greatest for maximum expiratory flow measurements and least for the FVC and FEV1. Maximum values from each set of tests reduced the variability. From these values, criteria and estimates were derived to evaluate significant intraindividual change. The PEF measurements were evaluated also to determine intraindividual changes. The coefficients of variation were only 2 percent to 14 percent. The peak flows obtained were shown to correlate well with the PVC peak flow.
Static deflation pressure-volume curves for the lungs of 104 subjects were satisfactorily fitted to an exponential function, V = Vmax - Ae-kP (where Vmax is volume V extrapolated to infinite transpulmonary pressure P, and A and k are constants). Subjects included 48 who met rigorous criteria defining normal, 35 were PiM phenotype for alpha-1-antitrypsin deficiency and 21 were PiMZ phenotype. The shape constant k was significantly related to age, whereas an index of curve position was not. Values for k corresponded closely to the data of other investigators suggesting that it was independent of size and insensitive to differences in experimental technique. Elevated values of k, indicative of emphysema, were no more prevalent among PiMZ subjects than among subjects with no alpha-1-anti-trypsin deficiency. The natural logarithm (1n) of k, rather than k itself, appears to provide a useful, normally distributed, expression of lung distensibility.
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Based on analysis of more than 2,500 forced vital capacity (FVC) maneuvers, we examined 2 aspects of the standards for spirometry recommended by the 1977 Snowbird Workshop concerning the timing of the FVC maneuver. We compared the forced expiratory volume in one sec (FEV1) when timing was initiated by the back extrapolation method with FEV1 when timing was initiated by flow or volume threshold to determine whether the latter offered a reliable equivalent. Although the mean differences appear to be relatively small, because of variability in initiating expiratory effort, neither alternative is likely to offer a uniformly accurate numeric equivalent to backward extrapolation. We also measured the volume expired before the initiation of the timing as a per cent of FVC to determine whether 10 per cent was a reasonable limit to apply for acceptability of a test. Although 2 SD from the mean of 4.35 per cent were well within this limit, it appears that the technician's judgment of acceptability is sufficient in most cases.