Why the FEV1/FVC ratio LLN as a percent of the predicted FEV1/FVC ratio is important

My medical director and I had a discussion today about where the cutoff for a normal FEV1/FVC ratio would be for a 93 year old patient of his. Part of the problem is that there are almost no reference equations for patients this age and the best you can usually do is to extrapolate. Another part is that anybody in their 90’s is a survivor and must have had good lung function throughout their life to reach that age, which means that they aren’t average so it’s not clear how well extrapolation actually works in this population. The final part is that the guidelines for PFT interpretation that are used by my lab were put into place about 40 years ago and reflect the thoughts at that time. I updated part of the guidelines with the 2005 ATS/ERS interpretation algorithm about 10 years ago, but the thresholds for normalcy (as well as the reference equations we use) still haven’t changed all that much. I’ve brought this issue up a number of times over the years (usually every time I get a new medical director) but haven’t gotten a consensus from the pulmonary physicians on either the need for change or for what threshold values should be used.

Anyway, both my medical director and I felt felt that the LLN for the FEV1/FVC ratio (when viewed as a percent of the predicted FEV1/FVC ratio) is probably lower for a 75 year old (and certainly for a 93 year old) than it is for a 25 year old, and that the current lab guidelines for interpretation were probably diagnosing airway obstruction in the elderly more often than they should. My lab currently uses the NHANESIII reference equations for spirometry however, and I wasn’t sure they showed this particularly well since the equations for the FEV1/FVC ratio and its LLN are quite simplistic compared to those for FVC and FEV1.

The NHANESIII reference equations were published in 1999 and at that time they were derived from the largest population that had ever been studied (7428 subjects, 40.9% male, 59.1% female) and with the most sophisticated statistical analysis that had been used up until that time. In 2012 however, the Global Lung Function Initiative (GLI) released a set of reference equations using data obtained from 73 centers world-wide on 97,759 subjects (44.7% male, 55.3% female). Statistical analysis of the GLI data was performed using the Lambda, Mu, Sigma (LMS) approach and a set of equations were derived that covered ages 3 to 95.

I have some reservations about how well the GLI equations match the population served by my lab but it’s a moot point whether I like them or not since even now, 5 years after the GLI equations were published, my lab’s software has not been updated to include them. The reason for this is that the GLI spirometry equations use what are called “splines” to generate the spirometry reference values and these are taken from a look-up table. My lab’s software does have an equation editor but it will not accommodate lookup tables so the GLI equations can’t be added. I’m sure our equipment manufacturer could get around this if they really wanted to, but so far it hasn’t happened.

I do have a lot of respect for the GLI equations however, and think that the overall view they give of the normal distribution of FVC, FEV1 and the FEV1/FVC ratio is far more correct than those of any prior studies. Using a spreadsheet tool downloaded from the GLI that lets me generate the GLI spirometry predicted values and the NHANESIII reference equations I decided to take a closer look at their predicted FEV1/FVC ratios and their LLNs.

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Another post-BD FVC conundrum

Okay, this may be wrong but at the moment I’m can’t seem to find a reason why it should be. A report like this came across my desk a couple of days ago.

Observed: %Predicted: Post-BD: %Predicted: %Change:
FVC: 4.59 94% 4.87 100% +6%
FEV1: 3.38 89% 3.58 94% +6%
FEV1/FVC: 73.6 95% 73.5 95% 0

Not particularly unusual and it would usually be interpreted as being within normal limits without a significant post-BD change. If you calculate the FEV1/VC ratio using the pre-BD FEV1 and the post-BD FVC however, it’s 89% of predicted and this indicates mild airway obstruction. But you’re not supposed to use the post-BD FVC this way, are you?

Well, why not?

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Normal or obstruction?

I had finished reviewing a pre- and post-BD spirometry report yesterday and was about to toss it on my out pile when I noticed something a bit odd about the post-BD results. I pulled it back and spent some time trying to decide if the interpretation needed to be changed but after a lot of internal debate I finally let it go as it was. I’ve continued to think about it however, and although I’m not sure that was the right decision I still haven’t come up with a clear answer.

Here’s what I saw:

Observed: %Predicted: Post-BD: %Predicted: %Change:
FVC: 3.70 97% 3.91 103% +6%
FEV1: 2.82 94% 2.79 93% -1%
FEV1/FVC: 76 95% 71 89% -6%
PEF: 6.62 94% 7.19 102% +9%
Exp. Time: 10.92 11.15

The reported pre-BD and post-BD results were from good quality tests and met the criteria for repeatability. My problem is that the baseline results were normal but if I had seen the post-BD results by themselves I would have considered them to show mild airway obstruction.

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Is there airway obstruction when the FEV1 is normal?

I’ve been reviewing the literature on PFT interpretation lately and in doing so I ran across one of the issues that’s bothered me for a while. Specifically, my lab has been tasked with following the 2005 ATS/ERS guidelines for interpretation and using this algorithm these results:

Observed: %Predicted: LLN: Predicted:
FVC: 2.83 120% 1.76 2.36
FEV1: 1.77 100% 1.26 1.76
FEV1/FVC: 63 84% 65 75

would be read as mild airway obstruction.

Although it’s seems odd to have to call a normal FEV1 as obstruction I’ve been mostly okay with this since my lab has a number of patients with asthma whose best FVC and FEV1 obtained at some point in the past were 120% of predicted or greater but whose FEV1 frequently declines to 90% or 100% of predicted. In these cases since prior studies showed a normal FEV1/FVC ratio then an interpretation of a mild OVD is probably correct even though the FEV1 itself is well above the LLN, and this is actually the situation for this example.
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Does the FEV1/SVC ratio over-diagnose airway obstruction?

A low FEV1/VC ratio is the primary indication for airway obstruction.

ATS_ERS_Interpretation_Algorithm

From ATS/ERS Interpretive Strategies for Lung Function tests, page 956.

The ATS/ERS statement on interpretation says

The VC, FEV1, FEV1/VC ratio and TLC are the basic parameters used to properly interpret lung function (fig. 2). Although FVC is often used in place of VC, it is preferable to use the largest available VC, whether obtained on inspiration (IVC), slow expiration (SVC) or forced expiration (i.e. FVC).”

I understand and in general agree with the idea of using the largest VC regardless of where it comes from and this is because the FVC is often underestimated for any number of good (and not so good) reasons. When this happens the FEV1/FVC ratio will be overestimated and airway obstruction will be under-diagnosed. However the ATS/ERS statement is also grounded in the notion that all vital capacities (FVC, SVC, IVC) are the same and this isn’t necessarily true. The problem comes from the fact that the predicted values and lower limit of normal (LLN) for the FEV1/VC ratio always come from reference equations for FEV1/FVC ratios. Because the SVC (and IVC) are usually larger than the FVC this means there is at least the potential for airway obstruction to be over-diagnosed.

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COPD and the FEV1/FVC ratio. GOLD or LLN?

Everyone uses the FEV1/FVC ratio as the primary factor in determining the presence or absence of airway obstruction but there are differences of opinion about what value of FEV1/FVC should be used for this purpose. Currently there are two main schools of thought; those that advocate the use the GOLD fixed 70% ratio and those that instead advocate the use the lower limit of normal (LLN) for the FEV1/FVC ratio.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has stated that a post-bronchodilator FEV1/FVC ratio less than 70% should be used to indicate the presence of airway obstruction and this is applied to individuals of all ages, genders, heights and ethnicities. The official GOLD protocol was first released in the early 2000’s and was initially (although not currently) seconded by both the ATS and ERS. The choice of 70% is partly happenstance since it was one of two fixed FEV1/FVC ratio thresholds in common use at the time (the other was 75%) and partly arbitrary (after all why not 69% or 71% or ??).

The limitations of using a fixed 70% ratio were recognized relatively early. In particular it has long been noted that the FEV1/FVC ratio declines normally with increasing age and is also inversely proportional to height. For these reasons the 70% threshold tends to over-diagnose COPD in the tall and elderly and under-diagnose airway obstruction in the short and young. Opponents of the GOLD protocol say that the age-adjusted (and sometimes height-adjusted) LLN for the FEV1/FVC ratio overcomes these obstacles.

Proponents of the GOLD protocol acknowledge the limitation of the 70% ratio when it is applied to individuals of different ages but state that the use of a simple ratio that is easy to remember means that more individuals are assessed for COPD than would be otherwise. They point to other physiological threshold values (such as for blood pressure or blood sugar levels) that are also understood to have limitations, yet remain in widespread use. They also state that it makes it easier to compare results and prevalence statistics from different studies. In addition at least two studies have shown that there is a higher mortality of all individuals with an FEV1/FVC ratio below 70% regardless of whether or not they were below the FEV1/FVC LLN. Another study noted that in a large study population individuals with an FEV1/FVC ratio below 70% but above the LLN had a greater degree of emphysema and more gas trapping (as measured by CT scan), and more follow-up exacerbations than those below the LLN but above the 70% threshold.

Since many of the LLN versus GOLD arguments are based on statistics it would be useful to look at the predicted FEV1/FVC ratios in order to get a sense of how much under- and over-estimation occurs with the 70% ratio. For this reason I graphed the predicted FEV1/FVC ratio from 54 different reference equations for both genders and a variety of ethnicities. Since a number of PFT textbooks have stated that the FEV1/FVC ratio is relatively well preserved across different populations what I initially expected to see was a clustering of the predicted values. What I saw instead was an exceptionally broad spread of values.

Male_175cm_Predicted

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Airway obstruction and the FVC

Spirometry is the most commonly performed (and mis-performed) pulmonary function test around the world. The apparent simplicity of spirometry is misleading since there are numerous subtleties that have a significant effect on the results.

I suspect that when the FVC is thought about it is most often considered to be an index towards the total capacity of the lung. That’s certainly true in it’s own way, but the FVC is actually a critically important factor when determining airway obstruction. I’ve had a number of reports across my desk lately where the patient had a reasonably large change in FVC when compared to their last visit but little change in FEV1, and this has made a difference in how the results are interpreted. For example:

Visit 1: Observed: %Predicted: Predicted:
FVC: 4.27 87% 4.91
FEV1: 3.36 84% 3.99
FEV1/FVC: 79 96% 82
Visit 2: Observed: %Predicted: Predicted:
FVC: 4.67 95% 4.91
FEV1: 3.38 85% 3.99
FEV1/FVC: 72 88% 82

Although the change in FVC is not significant by my lab’s standards (+0.40 L, +9%) and the FEV1 has hardly changed at all, the FEV1/FVC ratio has gone from being within normal limits to being under the LLN and therefore showing mild airway obstruction. Continue reading

Underutilized spirometry, missed opportunities

A friend is taking her father to a PFT lab (2500 miles away from where I am the moment so I couldn’t go along with them) because he has been short of breath for a couple of years, but oddly enough, only when lying on his side. I expect that despite these rather specific symptoms he will only get routine spirometry. I don’t necessarily fault the PFT Lab he’s going to for this, partly because physician orders often don’t include specifics, partly because they may not have the facilities to perform supine or lateral spirometry, and partly because its not clear lateral spirometry would show anything.

I don’t think that my lab is necessarily any better. We have only one room with an exam table that allows us to perform positional spirometry and that is largely because of the ALS patients we regularly see. Even so, unless we received specific orders to perform supine or lateral spirometry it’s unlikely that one of our technicians would think it was necessary and then take it on themselves to perform it. That itself is part of the problem not only for my lab but for the field of Pulmonary Function testing in general (but that’s another story).

The real problem however, is that the way in which spirometry is performed around the world is focused almost exclusively on detecting expiratory airway obstruction. It may be true that airway obstruction is primarily expiratory, but this ignores that fraction of individuals who have some degree of inspiratory obstruction. It also overlooks those individuals whose FVC is underestimated and FEV1/FVC ratio overestimated due to some degree of gas trapping. It also overlooks individuals that have positional airway obstruction that is not evident in the upright position.

We’ve fallen into the trap of thinking that there’s only one way to perform spirometry, and this is a mistake.

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RVD’s and OVD’s can’t mix without the FEV1/FVC ratio

The patients whose reports I review have always been very accommodating. An issue of one kind or another catches my attention and before I know it I find several more reports that are similarly involved. Thanks to our patients I’ve had a number of reports come across my desk recently that showed a combination of restrictive and obstructive defects. This particular one may not be the best possible example but it seems to illustrate several points fairly well.

Observed: %Predicted: Predicted:
FVC (L): 1.12 40% 2.80
FEV1 (L): 0.75 35% 2.16
FEV1/FVC (%): 67 86% 78
TLC (L): 1.92 42% 4.54
FRC (L): 1.18 48% 2.47
RV (L): 0.76 44% 1.73
RV/TLC (%): 40 104% 38

Interpreting results like this as combined (or mixed) defects using the ATS/ERS algorithm seems relatively straightforward.

ATS-ERS Algorithm 2

From Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of pulmonary function testing. Interpretive strategies for lung function tests. Eur Respir J 2005; 26, page 956

The algorithm starts by using the FEV1/FVC ratio to determine whether obstruction is present and only then considers whether or not the FVC and TLC are normal. It occurred to me however, that this assumes that the normal range of the FEV1/FVC ratio is preserved when TLC decreases below normal. Given the markedly different causes of restrictive lung disease it would seem that saying that the FEV1/FVC ratio should remain within the normal range over a relatively broad range of lung capacities (and without necessarily knowing the cause for any reduction) seems a bit far-fetched. Interestingly enough however, it actually turns out to be reasonably true.

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The NHANESIII FEV1/FVC ratio and height, revisited

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.

Male_50yo

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