Historical review: the carbon monoxide diffusing capacity (DLCO) and its membrane (DM) and red cell (Theta.Vc) components.

The single breath carbon monoxide diffusing capacity (DLCO sb), also called the transfer factor (TLCO), was introduced by Marie and August Krogh in two papers (Krogh and Krogh, Skand. Arch. Physiol. 23, 236-247, 1909; Krogh, J. Physiol., Lond. 49, 271-296, 1915). Physiologically, their measurements showed that sufficient oxygen (by extrapolation from CO) diffused passively from gas to blood without the need to postulate oxygen secretion, a popular theory at the time. Their DLCO sb technique was neglected until the advent of the infra-red CO meter in the 1950s. Ogilvie et al., J. Clin. Invest. 36, 1-17, 1957 published a standardized technique for a 'modified Krogh' single breath DLCO, which eventually became the method of choice in pulmonary function laboratories. The Roughton-Forster equation (J. Appl. Physiol. 1957, 11, 290-302) was an important step conceptually; it partitioned alveolar-capillary diffusion of oxygen (O2) and carbon monoxide (CO) into a membrane component (DM) and a red cell component (theta.Vc) where theta is the DLCO (or DL(O2)) per ml of blood (measured in vitro), and Vc is the pulmonary capillary volume. This equation was based on the kinetics of O2 and CO with haemoglobin (Hb) in solution and with whole blood Hartridge and Roughton, Nature, 1923, 111, 325-326; Proc. R. Soc. Lond. Ser. A, 1923, 104, 376-394; (Proc. R. Soc. Lond. Ser. B, 1923, 94, 336-367; Proc. R. Soc. Lond. Ser. A 1923, 104, 395-430; J. Physiol., Lond. 1927, 62, 232-242; Roughton, Proc. R. Soc. Lond. Ser. B 1932, 111, 1-36) and on the relationship between alveolar P(O2) and 1/DLCO. Subsequently, the relationship between DL(O2) (Lilienthal et al., Am. J. Physiol. 147, 199-216, 1946) and DL(CO) was defined. More recently, the measurement of the nitric oxide diffusing capacity (DLNO) has been introduced. For DL(O2) and DLNO the membrane component (as 1/DM) is an important part of the overall diffusion (transfer) resistance. For the DLCO, 1/theta.Vc probably plays the greater role as the rate limiting step. A crucial question, the effect of unstirred plasma layers on the 'true' value of thetaCO in vivo, has not been resolved, but this does not detract from the clinical role of the DLCO sb (TLCO) as an essential test of lung function.

Revisiting "respiratory function in emphysema in relation to prognosis".

BACKGROUND: The 1956 paper by DV Bates, JMS Knott and RV Christie, "Respiratory function in emphysema in relation to prognosis" Quart J Med 1956;97:137-157 is largely reprinted with a commentary by the first author, Dr David Bates. Although the pathology of emphysema was well recognized at the time, the clinical diagnosis and assessment of its severity were known to be imprecise; physiological measurements assessing and following the clinical course had not been established. The study aimed to follow systematically a group of patients, selected by clinical criteria using standardized clinical and physiological techniques, over four years and correlate physiological and clinical changes in relation to prognosis and eventually to postmortem findings. Fifty-nine patients were recruited to an emphysema clinic at St Bartholomew's Hospital, London, England. Inclusion criteria were dyspnea without other causes and no cor pulmonale present. Patients' symptoms were assessed by a standardized questionnaire, and measurements were taken of lung volumes, maximal ventilatory volume, carbon monoxide diffusing capacity at rest, exercise and oxygen saturation by oximetry. During the four years of the study, 17 patients died (actuarial expected - four) and 13 presented with signs of pulmonary heart failure. All postmortem examinations (n=9) showed advanced emphysema. A seasonal variation in dyspnea was established (the period included the infamous 1952 London smog). Four patients improved, and the remainder were unchanged or deteriorated. Close relationships were shown between dyspnea and function results, particularly for the diffusing capacity of lungs for carbon monoxide (DLCO). A comparison among a group of patients with chronic bronchitis without dyspnea showed that the DLCO discriminated between them. A loss of the normal increase in DLCO during exercise was shown in emphysema. IMPORTANCE: The study showed the value of standardized clinical and physiological techniques in following chronic obstructive pulmonary disease patients, and of separating the effects of airflow obstruction from impaired gas exchange function. Impaired gas exchange was shown to be important in influencing prognosis.

Lines that connect: assessing the causality inference in the case of particulate pollution.

The question of when it would be appropriate to conclude that the associations between particulate pollution and various outcomes (including mortality) should be judged as causal in nature has been difficult and controversial. Although such a judgment must be subject to revision, the volume of new information and new experimental findings has been so great that such a reevaluation is required at frequent intervals. The useful summary by Gamble [PM(2. 5) and Mortality in Long-Term Prospective Cohort Studies: Cause-Effect or Statistical Associations? Environ Health Perspect 106:535-554 (1998)] of the reasons why a causal inference was, in his opinion, not justified provides a basis for reevaluation in the light of new data. Such a reexamination indicates that the associative evidence is now stronger and that the biologic basis for a number of adverse effects has now been demonstrated. All of the useful guideline criteria customarily applied to such questions seem to have been met, although there is still much to be learned about interactive effects and the possibility of statistical thresholds.

Unrecognized asbestos-induced disease.

It is being slowly recognized that there is serious under-reporting of cancers that are occupationally related, in the sense that they would not have occurred without the occupational exposure. Data from the Workers' Compensation Boards of New South Wales in Australia and British Columbia in Canada relating to disease attributable to asbestos exposure indicate that in both jurisdictions the ratio of lung cancer cases to mesothelioma cases is much lower than epidemiological studies indicate must be occurring. Over the period from 1980 to 1994, if both jurisdictions are considered together, about 1,207 cases of lung cancer that would not have occurred without asbestos exposure went unrecognized as occupationally related. The data also suggest that it is unlikely that radiological asbestosis should be regarded as a necessary condition for there to be an increased risk of lung cancer following asbestos exposure.

Adverse health impacts of air pollution--continuing problems.

Evidence has been published that current levels of fine particulate pollution are associated with a wide range of adverse health outcomes, including accelerated mortality. Tropospheric ozone, often in association with aerosol sulfates, is similarly and independently associated with increased emergency visits and hospital admissions for acute respiratory disease, and there are sound reasons for suspecting that asthma may be worsened by exposure to it. Whether nitrogen dioxide is important at current levels in inducing adverse health effects is unclear. Although the combination of sulfur dioxide and particulate pollution that results from uncontrolled coal burning has been known for 30 years to be harmful, the independent role of sulfur dioxide cannot yet be precisely defined. A first report has appeared that ambient levels of volatile organic compounds may be associated with symptoms. Current efforts to assess the costs, in economic terms, of the adverse health effects attributable to air pollution are likely to be intensified.

Observations on asthma.

A review of the present understanding of asthma leads to the following conclusions: an elevated IgE is the principal risk factor in the development of childhood asthma; secondary exposure to a wide range of environmental agents (including indoor bioallergens) accounts for the variations in prevalence; prevalence (defined by a positive answer to the question "Have you ever had doctor-diagnosed asthma?") ranges between 4 and 8% in children. Black children have a slightly higher prevalence than white children in the United States, and in both races boys have a higher prevalence than girls. A high prevalence is found in Puerto Rican children in the United States. Patterns of utilization of health care resources (hospital emergency departments, individual physicians, etc.) are dependent on economic circumstances. Low-income children have higher annual morbidity (days in hospital, days off school, etc.) than higher income children and are more dependent on hospital emergency departments for primary care. Relatively little is known about nonatopic asthma in adults, although virus infections and occupational exposures play some part in its induction. There are some striking examples of asthma attack periodicity, and much may be learned from these. Hospital admissions for asthma have increased in many regions over the past 15 years; it is unlikely that this represents the increased admission of milder cases and hence would indicate that asthma has become more severe. This is likely to be a more sensitive indicator of change than mortality. Associations between indices of health effects and air pollutants indicate that these are probably playing a role in the worsening of asthma. Adverse effects related to SO2 and NO2 exposures have been documented, and fine particulate pollution (PM10) is also associated with worsening of asthma. Ozone is an intense respiratory irritant, and, together with acid aerosols, may well be playing a role in the worsening of asthma. It is not known whether any of these agents are affecting prevalence.

The effects of air pollution on children.

Air pollutants have been documented to be associated with a wide variety of adverse health impacts in children. These include increases in mortality in very severe episodes; an increased risk of perineonatal mortality in regions of higher pollution, and an increased general rate of mortality in children; increased acute respiratory disease morbidity; aggravation of asthma, as shown by increased hospital emergency visits or admissions as well as in longitudinal panel studies; increased prevalence of respiratory symptoms in children, and infectious episodes of longer duration; lowered lung function in children when pollutants increase; lowered lung function in more polluted regions; increased sickness rates as indicated by kindergarten and school absences; the adverse effects of inhaled lead from automobile exhaust. These impacts are especially severe when high levels of outdoor pollution (usually from uncontrolled coal burning) are combined with high levels of indoor pollution. In developed countries, where indoor pollution levels are lower, increasing traffic density and elevated NO2 levels with secondary photochemical and fine particulate pollution appear to be the main contemporary problem. By virtue of physical activity out of doors when pollution levels may be high, children may experience higher exposures than adults. Air pollution is likely to have a greater impact on asthmatic children if they are without access to routine medical care.

Health effects of particulate air pollution: time for reassessment?

Numerous studies have observed health effects of particulate air pollution. Compared to early studies that focused on severe air pollution episodes, recent studies are more relevant to understanding health effects of pollution at levels common to contemporary cities in the developed world. We review recent epidemiologic studies that evaluated health effects of particulate air pollution and conclude that respirable particulate air pollution is likely an important contributing factor to respiratory disease. Observed health effects include increased respiratory symptoms, decreased lung function, increased hospitalizations and other health care visits for respiratory and cardiovascular disease, increased respiratory morbidity as measured by absenteeism from work or school or other restrictions in activity, and increased cardiopulmonary disease mortality. These health effects are observed at levels common to many U.S. cities including levels below current U.S. National Ambient Air Quality Standards for particulate air pollution.

Reanalysis of a longitudinal study of pulmonary function in coal miners in Lorraine, France.

Multiple methods of statistical analysis were applied on data collected on 384 coal miners from the Lorraine region of France. Despite the irregularity of timing of visits over the follow-up period, similar estimates of decline resulted irrespective of the statistical method used. Deceased smokers showed the highest rates of decline in forced expiratory volume during 1 second (FEV1) of 65 to 72 ml/yr, whereas the alive non-smokers had the lowest decline estimates of 42 to 48 ml/yr. Estimates of FVC decline were found to parallel those of FEV1. For about one-half of the cohort, data were available to compare FEV1 decline before and after retirement using a profile analysis. Based upon a "differencing" method of regression, retirement from the coal mine had the effect of decreasing the rate of decline for those who had never smoked; smokers, however, showed an increasing rate of decline.

Respiratory hospital admissions and summertime haze air pollution in Toronto, Ontario: consideration of the role of acid aerosols.

A study of air pollution and daily hospital admissions for respiratory causes was conducted in Toronto, Ontario. Fine aerosol (da < 2.5 microns) samples were collected daily at a central city site during July and August 1986, 1987, and 1988 and were subsequently extracted and analyzed for daily particulate phase aerosol strong acidity (H+) and sulfates (SO4 =). Daily counts of respiratory admissions to 22 acute care hospitals and daily meteorological and environmental data (e.g. ozone [O3], total suspended particulate matter [TSP], and thoracic particle mass [PM10] were also obtained. Regression analyses indicated that only the O3, H+, and SO4 = associations with respiratory and asthma admissions remained consistently significant after controlling for temperature. Even after excluding days with maximum 1-hr O3 > 120 ppb, O3 was still strongly significant. In the various model specifications considered, the relative particle metric strengths of association with admissions were generally H+ > SO4 = > FP > PM10 > TSP, indicating that particle size and composition are of central importance in defining the adverse human health effects of particulate matter. On average, summertime haze air pollution was associated with 24% of all respiratory admissions (21% with O3, 3% with H+). On peak pollution days, however, aerosol acidity yielded the highest relative risk estimates (e.g., RR = 1.5 at 391 nmole/m3 H+), and summertime haze was associated with roughly half of all respiratory admissions.

Detection of chronic respiratory bronchiolitis in oxidant-exposed populations: analogy to tobacco smoke exposure.

Studies in nonhuman primates indicate that one pathophysiologic consequence of ozone exposure is chronic bronchiolitis in terminal bronchioles. Modeling dosimetry suggests that a similar phenomenon is possible in humans. These findings may constitute an important analogy to the respiratory bronchiolitis that is associated with tobacco smoking in young adults. This analogy could form the basis for future research related to chronic respiratory health effects of ozone. The smoking data are reviewed and several research strategies are proposed that will be developed more fully in subsequent articles in this volume.