I was reading James Hansen’s textbook on pulmonary function testing and ran across a spot where he made a minor criticism of the NHANESIII (Hankinson et al) reference equations for the FEV1/FVC ratio. Specifically he noted that the NHANESIII equation ignored height and only used age as a variable but that when he compared the directly calculated FEV1/FVC ratio with one indirectly derived from predicted FEV1 and FVC there was a discrepancy across the normal ranges of height of up to 2.4%.
I had also noticed this discrepancy and wrote about it a while back but at the time I’d only been discussing my lab’s adoption of the NHANESIII reference equations. Hansen’s observation intrigued me, so I decided to re-visit this issue more systematically.
To do this I’ve taken 23 different reference equations for men and women and a variety of ethnicities and plotted the change in the FEV1/FVC ratio versus height, and then repeated this across a range of ages.
When DLCO tests are performed my lab’s standard policy to average two or more results that meet the criteria for quality and reproducibility. It is not unusual for us to perform three DLCO tests and have all of them meet quality criteria but to have one test result that is higher than the other two. Unlike spirometry tests, bigger isn’t necessarily better for DLCO, so in a circumstance like this we will average the two closest results rather than choose the highest result. Even though the higher test results can come from a DLCO test with good quality, I think that reproducibility trumps this and that choosing by reproducibility gives us results that are more clinically reliable.
When I review spirometry results and either lung volumes or a DLCO test has also been performed, I will always check the Slow Vital Capacity(SVC) from the lung volumes and the Inspiratory Volume (Vinsp) from the DLCO test to see if they are larger than the reported Forced Vital Capacity. If either of them is I will manually re-calculate the FEV1/VC ratio to see if it indicates the presence of airway obstruction. This is in line with the ATS-ERS recommendations to use the largest Vital Capacity, regardless of the source, for the FEV1/VC ratio.
I have been reviewing the raw test data for all DLCO tests (as well as all the lung volume tests and regular spot checks on spirometry) performed in my lab for at least the last year. Since our software and hardware upgrade a year and a half ago we’ve found a number of problems that have significant effects on the DLCO test results. Depending on the problem they are capable of causing the results to be over- or under-estimated. All of the technicians performing the tests are now well aware of these problems and there haven’t been any problematic DLCO tests selected for a while. Nevertheless, I always check the raw data just to be sure.
Today, I ran across a report that looked quite straightforward. A set of spirometry and DLCO tests had been performed on a frequent-flier patient with pulmonary fibrosis. The patient has restrictive lung disease and lung volumes measured about a year ago were 64% of predicted. Even though the patient’s FVC has decreased since then there is no clinical reason to repeat the lung volume measurements. The results looked like this:
The FEV1 and FEV1/FVC ratio seems to have become the predominant, if not the sole factor for determining the presence of airway obstruction. It is true that a reduced FEV1/FVC ratio provides a strong and reliable signal for this purpose but its limitations have also been recognized for quite a while. The most obvious one is that the FEV1/FVC ratio will be falsely elevated when the FVC is underestimated. This is the primary factor driving the interest in FEV6 and the FEV1/FEV6 ratio. Less well appreciated is the fact that there are many causes and sites within the airways that can be involved in airway obstruction and that the focus on the FEV1/FVC ratio may cause certain forms of airway obstruction to be overlooked.
The FEF25-75 (aka MMEF) was originally proposed as way to determine the presence of small airways disease but it has since been shown to be an unreliable indicator. Most of the pulmonary physicians I work with have expressed doubt that there is such a thing as small airways disease but that doesn’t mean that some patients don’t have mild airway obstruction that is not evident when assessed solely by the FEV1/FVC ratio.
The Slow Vital Capacity (SVC) maneuver is usually performed as part of lung volume measurements. It is not unusual for the SVC to be larger than the FVC, particularly in patients with airway obstruction. This can have a bearing on the FEV1/FVC ratio and in fact the ATS-ERS recommendations for PFT interpretation say that the largest vital capacity value regardless of which test it comes from should be used to calculate the FEV1/VC ratio. When I review a full panel of tests (FVC, lung volumes, DLCO) I always check to see if the SVC or IVC (from the DLCO test) are larger than the FVC and then re-calculate the FEV1/FVC ratio and its percent predicted if they are. Test results that at first glance look normal will instead show airway obstruction often enough when this has been done that the time spent going through this process is worthwhile.
This only works however, when I have a full panel of tests to extract other vital capacities from. Patients that show airway obstruction when their FEV1/VC ratio is re-calculated have often had only spirometry performed on prior visits and their spirometry results were considered to be within normal limits at those times. Our lab software lets us select and report the “best” FVC and FEV1 from a series of spirometry efforts so this raises an interesting question and that is when and how often should a SVC maneuver be performed instead of a FVC maneuver during a spirometry session in order to get and report the largest VC?
Although the authors of the Global Lung Function Initiative (GLFI) study acknowledge the effect of height on their reference equations the range and distribution of heights in its study populations was not included in the report. This was a similar problem for the NHANESIII reference equations since the height range was never reported within the text of the original report however it did include scatter graphs showing the range of heights. These graphs imply the height range was 162 to 194 cm (64” to 76”) for caucasian males and 145 to 180 cm (57” to 71”) for caucasian females. Using the extremes of these height ranges it is interesting to see how the GLFI reference equations compare to the NHANESIII reference equations.
The Global Lung Function Initiative (GLFI) was established by the European Respiratory Society in 2008 with the goal of establishing a truly worldwide set of reference equations for spirometry. Its results were released in the December 2012 issue of the European Respiratory Journal. Although the reference equations presently apply only to Caucasians, African-Americans and northern and southern Asians, it will likely be updated with Hispanic, African and Polynesian data within the next couple of years.
This has been a massive undertaking involving spirometry data from 72 different testing centers in 33 countries. The data has been subjected to rigorous quality control and an extensive, sophisticated statistical analysis and will likely become the standard reference equation set for spirometry testing in Pulmonary Function labs around the world.
Over forty years ago when I started to learn about pulmonary function testing I was taught about the nuts and bolts of the tests, not where the tests came from or how they came into existence. Spirometry and the FVC, FEV1 and FEV1/FVC ratio have always appeared to be the core elements of pulmonary function testing and seemed most likely to have been scratched on the wall of the first paleolithic PFT lab cave. I have been reviewing a lot of older research papers lately, including several historical reviews, and was quite surprised to find out how recent both FEV1 and the FEV1/FVC ratio really are.
The first version of the modern spirometer (a counter-weighted volume displacement water seal spirometer) was developed by John Hutchinson in England around 1844. He performed vital capacity measurements on over 3000 people and in 1846 published a paper where he showed (among other things) the linear relationship of vital capacity to height. Different versions of Hutchinson’s spirometer were developed by other researchers in the following decades but even through the 1920’s the only measurement that was ever made with a spirometer remained just the vital capacity.
FEV6 (the volume of air forcefully exhaled after 6 seconds) has been proposed as a replacement or surrogate for FVC in spirometry. Given that using FEV6 would simplify and speed up the spirometry test this is a seductive notion.
The use of an expired volume with a fixed expiratory time as a replacement for FVC was proposed at least 25 years ago, although at that time FEV7 was proposed as being slightly more accurate than FEV6. The first reference values for FEV6 however, were not available until the results from NHANESIII study were made available in 1999 and most studies of FEV6 post-date that.
When we went through our hardware and software upgrade last August, one of the changes we made was to stop reporting the FEF25%-75% (AKA MMEF, MMFR, MMF). The pulmonary physicians had long since stopped using this value when assessing spirometry results and we had kept it on our reports as long as we did only for inter-laboratory compatibility. Along with other changes we made at that time we decided it was time to drop the FEF25%-75% off our reports.
FEF25%-75% has been used to assess “small airways disease” but more than one of our pulmonary physicians has said that they don’t believe there is such a thing. I’m not a clinician but I’ve always felt that tests and results need to be clinically useful in order to be performed or reported and more than one study has shown little correlation between anatomical findings and FEF25%-75%.
Regardless of whether or not small airways disease is an actual entity my first objection to the FEF25%-75% has to do with the concept that it measures flow in small airways when for most patients it lies within their FEV1. For this reason it has never been clear to me what the FEF25%-75% is measuring that the FEV1 isn’t. More importantly, I have significant concerns about the limitations involved in measuring the FEF25%-75% in the first place.
The FEV1/FVC ratio is used to estimate the presence and degree of airway obstruction. For well over thirty years my lab has used an FEV1/FVC ratio of 95% of predicted as the cutoff for normalcy. This value (carved onto a stone tablet by the way) had been brought to the lab by a founding physician who had come to the department from the NIH in the 1970’s. Since the software and hardware upgrade this summer our PFT Lab has switched to the NHANES III spirometry reference equations but we have so far resisted changing our 95% cutoff to the lower limit of normal (LLN). This is due in part to inertia but also in part to a mistrust in the concept of LLN. We have been steadily re-evaluating all of our testing criteria and have turned again to the FEV1/FVC ratio with the question as to whether our 95% cutoff is over-zealous or whether the LLN is too lax.
Strictly speaking LLN is a statistical concept. In the NHANES III study (and most others) it is computed as the mean predicted value minus 1.645 times the standard estimate of error. Unlike the reference equations for FVC and FEV1 which use both height and age as factors, the NHANES III reference equations for the FEV1/FVC ratio are derived solely from age. It is not clear to me this is completely correct and I have discussed some of the discrepancies between the NHANES III predicted FEV1/FVC ratio and height in a prior posting but it does make analyzing the LLN for the ratio easy.For adult, Caucasian males the reference equations are: