Recently a reader asked me a question about the FVC/DLCO ratio. To be honest I’d never heard of this ratio before which got me intrigued so I spent some time researching it. What I found leaves me concerned that a lack of understanding about reference equations may invalidate several dozen interrelated studies published over the last two decades.

Strictly speaking the FVC/DLCO ratio is the %predicted FVC/%predicted DLCO ratio (which is usually abbreviated FVC%/DLCO%) and it appears to be used exclusively by specialists involved in the treatment of systemic sclerosis and related disorders. Specifically, the ratio is used to determine whether or not a patient has pulmonary hypertension. The basic idea is that (quoting from a letter to the editor):

“As we know, in ILD both FVC and DLCO fall and their fall is proportionate, whereas in pulmonary arterial hypertension DLCO falls significantly and disproportionately to FVC.”

A variety of algorithms using the FVC%/DLCO% have been devised. Inclusion factors are usually an FVC < 70% of predicted and a DLCO (corrected for hemoglobin) < 60% of predicted. A number of different threshold values for FVC%/DLCO% have been published ranging from 1.4 to 2.2 with the differences appearing to be dependent on study population characteristics and the type of statistical analysis performed. It is thought that individuals meeting the inclusion factors with an FVC%/DLCO% ratio above the threshold most probably have pulmonary hypertension.

I could quibble about the notion that FVC and DLCO always decrease proportionally in ILD, but my biggest concern with this approach is that after reviewing 19 articles that discussed the FVC%/DLCO% ratio almost none of them indicated which FVC or DLCO reference equations were being used.

The very first study that made the observation about the FVC%/DLCO% ratio (Steen et al, 1992) did indicate that it used Morris’ reference equations for FVC and Burrows’ for DLCO; another article (Zisman et al) indicated that they used Crapo for FVC predicteds and Miller for DLCO predicteds; and one other article (Koh et al) referenced both Morris and Knudsen for FVC predicteds without indicating which was used and without indicating which DLCO reference equation was used.

Reference:	FVC Reference Equation:	DLCO Reference Equation:
[A]	No	No
[B]	No	No
[C]	No	No
[D]	No	No
[E]	No	No
[F]	No	No
[G]	No	No
[H]	No	No
[I]	No	No
[J]	No	No
[K]	Yes (Morris and Knudsen)	No
[L]	No	No
[M]	Yes (Morris)	Yes (Burrows)
[N]	No	No
[O]	No	No
[P]	No	No
[Q]	No	No
[R]	No	No
[S]	Yes (Crapo)	Yes (Miller)

That’s it. None of the other articles indicated which reference equations for FVC and DLCO were used. Unfortunately this leaves me with a strong impression that none of the authors (or journal reviewers for that matter) realize there are number of different (and conflicting) reference equations for both FVC and DLCO, and that this fact has significant implications for interpreting PFT results. One particularly telling comment was that the

“reference, actual, and percent predicted values … were extracted from the [Pulmonary Function] reports…”.

Which means to me that pulmonary function labs were not directly involved in the research and that the FVC and DLCO results came from routine testing.

This apparent ignorance is a concern since a number of the studies performed advanced statistical analyses determining the specificity and sensitivity of a variety of parameters, and in many cases gave very precise thresholds for the FVC%/DLCO% ratio. Any precision, unfortunately, is largely an artifact of which reference FVC and DLCO equations were actually used and I expect that much of the difference in published threshold values for the FVC%/DLCO% ratio are because the different studies used different reference equations (apparently without knowing they did).

As an example, for a 50 year old, 175 cm, Caucasian male, the average predicted FVC is 4.79 L (with a range from the reference equations I have on hand of 4.50 to 5.06) and the average predicted DLCO is 32.2 (ditto, ranging from 24.4 to 36.09). If you took an FVC that was 70% of the average predicted (3.35 L) and a DLCO that was 40% of the average predicted (12.88 ml/min/mmHg), depending on which reference equations you used the FVC%/DLCO% ratio could be anywhere from 1.25 to 2.09.

This is not the first time I’ve run across studies where the results or outcomes were based on the percent predicted of spirometry, lung volume or DLCO results but the reference equations were not identified. These tend to be relatively isolated examples and when I run across them I’ve usually thought the authors (and reviewers) were just being sloppy. Given the effect that reference equations have on results it has also meant I’ve taken any conclusions with a grain of salt.

This is the first time however, that I’ve run across an entire field of study that appears to be completely ignorant of the effect that reference equations have on PFT results. Admittedly, pulmonary function testing is somewhat unique when compared to other areas of medicine in that there are no universal reference values (kudos to the GLI people for trying but let’s be honest, since they’re still foundering on the reefs of ethnicity we’re not anywhere near there yet). And admittedly there is still a certain level of confusion among both pulmonary physicians and technologists on the subject of reference equations (but at least we know the problem exists). Even so, since the whole point of the FVC%/DLCO% ratio is to differentiate between ILD and ILD with pulmonary hypertension, weren’t any of these studies reviewed by a pulmonologist?

The basic concepts behind the FVC%/DLCO% ratio; that lung volumes tend to be reduced when ILD is present, and that DLCO tends to be reduced out of proportion to any decrease in lung volume when pulmonary hypertension is also present; fit well with existing knowledge. In addition percent predicted values are a way to “normalize” PFT results for a study population composed of different genders, ages and heights. The problem is that once you select a specific set of reference equations, any threshold values or other conclusions that you develop are entirely dependent on that selection and cannot be universally applied.

I try to keep up with the field of pulmonary function testing and at least skim the table of contents of a dozen or so medical journals every month looking for articles but I had never heard of the FVC%/DLCO% ratio before last week. So, an interesting thought is to wonder who else is using PFT results without understanding the problems with reference equations?

References.

[A] Beall AD, Nietert PJ, Taylor MH, Mitchell HC, Shaftman SR, Silver RM, Smith EA, Bolster MB. Ethnic disparities among patients with pulmonary hypertension associated with systemic sclerosis. J Rheumatology 2007; 34: 1277-1282.

[B] Coghlan JG et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: The DETECT Study. Ann Rheum Dis 2014; 73: 1340-1349.

[C] Corte TJ, Wort SJ, Wells AU. Pulmonary hypertension in idiopathic pulmonary fibrosis: a review. Sarcoidosis Vasculitis and Diffuse Lung Diseases 2009; 26: 7-19.

[D] Gladue H et al. Combination of echocardiographic and pulmonary function test measures improves sensitivity for diagnosis of systemic sclerosis-associated pulmonary arterial hypertension: analysis of 2 cohorts. J Rheumatology 2013; 40: 1706-1711.

[E] Goldberg A. Pulmonary arterial hypertension in connective tissue disorders. Cardiology In Review 2010; 18: 85-88.

Gupta R. Letter to the editor: Pulmonary function test as screening test for pulmonary artery hypertension in scleroderma patients. Rheum 2004; 43: 1315

[F] Hao Y et al. Comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis. Arthritis Research & Therapy 2015; 17: 7

[G] Hervier B et al. Pulmonary hypertension in antisythetase syndrome: prevalence, aetiology and survival. Eur Respir Dis 2013; 42: 1271-1782

[H] Hsu VM, Moreyra AE, Wilson AC, Shinnar M, Shindler DM, Wilson JE, Desai A, Seibold JR. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatology 2008; 35: 458-465.

[I] Hudson M et al. Comparison of different measures of diffusing capacity for carbon monoxide (DLCO) in systemic sclerosis. Clin Rheumatology 2013; 32: 1467-1474.

[J] Khanna D, Denton CP. Evidence-based management of rapidly progressing systemic sclerosis. Best Pract Res Clin Rheumatol 2010; 24(3): 387-400.

[K] Koh ET, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheum 1996; 35: 989-993.

[L] Risbano MG et al. Altered immune phenotype in peripheral blood cells of patients with scleroderma-associated pulmonary hypertension. Clin Trans Sci 2010; 3: 210-218.

[M] Steen VD, Graham G, Conte C, Owns G, Medsger TA. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum 1992; 35(7): 765-770.

[N] Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35: 35-42.

[O] Steen VD, Lucas M, Fertig N, Medsger TA. Pulmonary arterial hypertension and severe pulmonary fibrosis is systemic sclerosis with a nuclear antibody. J Rheumatology. 2007; 34: 2230-2235.

[P] Sivia N et al. Relevance of partitioning DLCO to detect pulmonary hypertension in systemic sclerosis. Plos One 2013; 8(10): e78001.

[Q] Thakkar V et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case control study. Arthritis Research & Therapy 2012; 14: R143.

[R] Walkey AJ, Ieong M, Alikhan M, Farber HW. Cardiopulmonary exercise testing with right-heart catheterization in patients with systemic sclerosis. J Rheumatology 2010; 37: 1871-1877.

[S] Zisman DA, Ross DJ, Belperio JA, Saggar R, Lynch JP, Ardehali A, Karlamangla AS. Prediction of pulmonary hypertension in pulmonary fibrosis. Respiratory Medicine 2007; 10: 2153-2159.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License