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Differences between Finnish and European reference values for pulmonary diffusing capacity.

Objectives. To compare European (ECSC) and Finnish reference values for single-breath diffusing capacity for carbon monoxide (DL(CO)). Study Design. Finnish reference values for DL(CO), specific diffusing capacity (DL(CO)/VA) and total lung capacity (TLC) were compared with ECSC reference values calculated for different age, height and weight groups. In addition, 10 healthy subjects performed the test with both the Finnish method (inhaled volume 90% of vital capacity, VC) and the ECSC method (inhaled volume 100% of VC). Methods. Percentual differences between the ECSC and Finnish reference values for DL(CO), TLC and DL(CO)/VA were calculated. The results of measurements of DL(CO) and TLC by using inhaled volume of 100% of VC and 90% of VC in 10 healthy subjects were compared. Results. The Finnish DL(CO) reference value for men was 3–12% and for women 8-20% smaller than the ECSC reference value. TLC calculated according to Finnish equations was 2-14% greater than that based on ECSC equations. The ECSC reference value for DL(CO)/VA was about 20% greater than the Finnish reference value in men and 30% greater than that in women. The 10 healthy subjects had significantly higher DL(CO) when measured according to the ECSC method as compared with the Finnish one (p & 0.004). Conclusions. The Finnish reference values for DL(CO) were about 10% smaller, but TLC 10% and DL(CO)/VA 20–30% greater than ECSC reference values in subjects of the same age, height, weight and gender. The difference in DL(CO) is explained by the different inhaled lung volumes used in the two methods, the difference in lung volumes probably arising from ethnic differences in thoracic cavity.


INTRODUCTION
In several human races, lung volume relative to height is smaller than in Europeans. The smallest height-related lung volume is in African Blacks and East Indians, and the largest in Scandinavians and inhabitants of the Highlands (1,2). Ethnic differences are nowadays being corrected for forced expiratory volume in one second (FEV1) and for forced vital capacity (FVC) according to international recommendations (1,3).
Diffusing capacity of the lungs (DL CO ) is used to assess the condition of lung tissue in several pulmonary diseases, for example, emphysema, alveolitis or other diseases of lung parenchyma. DL CO is usually measured with an indicator gas containing a small concentration of carbon monoxide (CO) in inhaled air to represent the gas exchange capacity of lung tissue, which is almost independent of ethnic origin (1,4,5). African Blacks may have a relatively low height-standardized diffusing capacity (6,7), as opposed to those from high altitudes, with a relatively high diffusing capacity (8)(9)(10), but good comparisons are lacking. Differences in diffusing capacity between different races are, however, anticipated to be minimal, which is why no correction has been recommended (1,(11)(12)(13).
During diffusing capacity measurement, lung volumes, total lung capacity (TLC) and residual volume (RV) are measured based on gas dilution. The relation of total diffusing capacity to alveolar volume (volume approaching TLC) is called specific diffusing capacity (DL CO /VA). Height-related TLC varies ethnically similarly to lung volumes measured in spirometry (3,14).

Comparison of reference values
We calculated reference values for DL CO for men with a height of 180 cm and women with a height of 165 cm, DL CO /VA for men with a height of 180 cm and a weight of 80 kg and women with a height of 165 cm and Comparison of diffusing capacity reference values a weight of 60 kg, and TLC for men with a height of 180 cm and a weight of 80 kg and women with a height of 165 cm and a weight of 60 kg, with ages ranging from 20 to 70 years according to Finnish (14) and ECSC (11,15)  The regression coefficients b1, b2, b3 and b4 for DL CO , DL CO /VA and TLC are reported in the reference publication (14) (A=age, H=height, W=weight). Calculation of the DL CO reference value is made according to age and height; in calculation of TLC and DL CO /VA reference values weight is also used.
The percentual difference was obtained when the ECSC reference value was subtracted from the Finnish one and the difference was divided by the ESCS reference value.
Analysis of effect of methods on diffusing capacity results DL CO , VC, TLC and DL CO /VA were measured for 10 healthy non-smoking volunteers working at the hospital (9 women and 1 man, age 48.7±12.8 y [mean and SD; range 21-69 y], height 165.3±5.2 cm, weight 69.5±9.3 kg) based on the Finnish method (14) with the patient inhaling 90% of VC and on the ECSC method with the patient inhaling 100% of VC. The diffusing capacity and volume results obtained by both methods were compared with each other with paired t-test.
The study protocol was approved by the Ethics Committee of Internal Medicine of the Hospital District of Helsinki and Uusimaa, and informed consent was signed by all volunteers.

Comparison of reference values
The ECSC reference value for DL CO was usually higher than the Finnish reference value, and this was particularly true in women (Fig. 1). By contrast, in short men the Finnish reference value was higher than the ECSC reference value.
The Finnish reference value for TLC was higher in men and women than the ECSC reference value (Fig. 2).
The Finnish reference value for DL CO /VA for men was lower (at its lowest, 22% lower) than that calculated according to the ECSC reference equation. In women, the Finnish DL CO /VA reference value was 27-33% smaller than the ECSC reference value (Fig. 3).
Comparison of methods TLC value was similar, but the DLco result was significantly lower (mean 3.46%, SD 3.09, range -1.2 -+9.4%), when the singlebreath test was performed with the Finnish method than when performed with the ECSC method ( Table I).

DISCUSSION
The Finnish reference value for TLC was higher than the ECSC reference value, as in an earlier study reporting reference values for FVC or FEV1 (17). The greater TLC values probably arise from differences in the thoracic cavity volume; the relation of the body and legs to the height of a person varies in different races (1,4,5). The ethnic differences may be genetic in origin. However, environmental factors might also explain the greater lung volume in Finns than in central Europeans. Increased habitual activity because of a cold climate as well as training of muscles in activities increasing inspiratory capacity, for example, skiing and swimming (1), may also have influenced the development of larger lung volume in Finns. As the age-and height-related Finnish TLC reference values were greater than the ECSC reference value, one could assume that also the Finnish reference value for DL CO would be greater. Based on our results this was not, however, the case; instead, the reverse was true, especially in young and old age groups.
The Finnish reference value of DL CO was in all age groups 3-20% smaller than the respective ECSC reference value.
The method used to obtain the Finnish reference value for DL CO was to restrict the inspiratory volume by 90% of the measured VC value. The measurement made with a restrictor was easy to perform and repeatable (18). However, the use of an inhalation restrictor explains the finding that the Finnish DL CO reference values (15) were lower than the ECSC reference values (11,16). This theoretical assumption gets more support from the experiment where diffusing capacity was determined for 10 healthy subjects with both methods; the diffusing capacity results were significantly lower when measured with the Finnish method. The difference varies, however, as is seen in Figure 1, depending on age and gender. Although the number of subjects participating in this experiment on the use of an inspiration restrictor was small, it might be argued that the DL CO of Finnish people living in northern Europe, partly in a circumpolar area, would not differ from that of middle Europeans. On the other hand, use Table I. Diffusing capacity measurement was performed twice for 10 healthy subjects. In one examination, the inspired volume (Vin) was 100% of maximal vital capacity (ECSC method) and in the other 90% of maximal vital capacity (Finnish method). The order of the measurements was random.

VC (l) VC (l) Vin
Vin TLC (l) TLC (l) DL CO (19) states that when the goal of inspiratory volume during the diffusing capacity test is 100% of VC, usually an inspiratory volume of only 90% of VC is gained. Based on this, the Finnish method, developed in the 1980s, that uses an inhalation restrictor at a volume level of 90% of measured VC seems to be good and practical. This method has been used in the Finnish reference values for DL CO (15).
Specific diffusing capacity (DL CO /VA) is a variable formed when DL CO is divided by alveolar volume. Alveolar volume (VA) is measured based on helium dilution in the held breath during the diffusing capacity test, and its volume is near the TLC value. The size of the thoracic cavity also influences the value of VA; the greater the VA value, the smaller the DL CO (15). Both reference values were collected for the most part in the mid-1970s, although the ECSC reference values include older material.
The Finnish reference values were used for all original inhabitants in Finland from along the southern coast to Lapland. No comparisons were conducted between Sami and Finnish people, for example, but the austere Lappish climate could be assumed to favour an increase in lung volume (1). Thus, theoretically, the Finnish reference values would be better suited for Sami people than for the ECSC ones.
International recommendations for ethnic correction of TLC reference value vary (1,(11)(12)(13), but usually TLC and RV reference values are corrected similarly to the FVC reference value (14). In the praxis of our laboratory, the diffusing capacity test on non-Finnish subjects was measured by the ECSC method (inspired volume, Vin, 100% of VC), and the ECSC reference values were used to interpret both diffusing capacity and lung volume results. For Finns, the diffusing capacity test was conducted using an inhalation restrictor at a level of Vin of 90% of VC and the Finnish reference values were used.
In 2005, the ATS/ERS recommended that new reference values for lung function be obtained (20). Although the Finnish reference values for DL CO (15) are methodologically of high quality, they are based on a rather small population, 296 males and 257 females. Moreover, age groups beyond 65 years are lacking, which is why in Finland new reference values will be collected. Until these new values are available, a correction based on ethnic and methodological differences will be included in assessment of the results of diffusing capacity tests.