The Global Initiative for Obstructive Lung Disease, GOLD, has set out to raise clinical interest in the diagnosis and management of chronic obstructive pulmonary disease across the world [ 1 ] with the aim "to improve prevention and treatment of this lung disease". The GOLD organisation is a committee of leaders in the field which is sponsored by 14 pharmaceutical companies with an interest in this area of medical practice. It was set up in 1997 with the collaboration of the National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization.
GOLD has arbitrarily defined COPD on clinical and physiological criteria that have been argued to be not based on scientific evidence [ 2 ]. The GOLD definition is that COPD should be considered in any patient with symptoms of cough, sputum production, or dyspnoea, and/or a history of exposure to risk factors for the disease. The diagnosis is confirmed by spirometry. GOLD state that a post bronchodilator FEV1 < 80% of the predicted value and an FEV1×100/FVC (FEV1%) of < 70% confirms the presence of airflow limitation that is not fully reversible.
The GOLD approach has been followed in the UK by the National Institute for Health and Clinical Excellence (NICE) setting out guidelines for the management of COPD [ 3 ] indicating that any patient over the age of 35 with a risk factor for COPD and presenting with exertional breathlessness, chronic cough, regular sputum production, frequent winter bronchitis or wheeze should have the diagnosis confirmed by spirometry.
Thus healthcare services are now being encouraged to make the diagnosis of this disease in the community.
There are two reasons to question the GOLD definition of airflow limitation. Firstly the use of percent of predicted values for FEV1 as a method for defining levels of abnormality of lung function is supported neither by the American Thoracic Society (ATS) nor by the European Respiratory Society (ERS) [ 4 ].
Secondly the use of a single cut off for FEV1% of 70% to define the limit of normality for this index is also not supported by the ATS or ERS.
The fact that the arbitrary definition may lead to an age bias in the diagnosis of COPD has already been presented [ 5-10 ] and we will now explore the reason behind this in more detail.
Defining Abnormality in Lung Function Data
When an individual records their spirometry for the first time the clinician will want to know if the result is acceptable. The clinician needs to know if the result is within the expected range for someone of their age, sex, height and ethnicity (all factors known to influence their lung function results).
|The best method to determine whether the result is normal is to calculate how far the subject's result is from their predicted value and express this in terms of the number of standard deviations from predicted the value is. This result is called the "Standardised Residual" (SR) and is given by:||SR = ( Recorded - Predicted )/RSD
RSD is the residual standard deviation from the prediction equation used. The term residual refers to the deviation a given subject's result is from the predicted value. In the Figure opposite the data value at 2.1 L has a residual from the predicted line for this subject's age and height of 1.8 L. This residual is then standardised by the spread (standard deviation) of these residuals found in the population used for the prediction.
Calculating the predicted value is usually done using a prediction equation taken from a population of comparable subjects and using equipment similar to that used for the subject's recording. For example the ECCS equation for FEV1 in men [ 11 ] is:
Predicted FEV1 = 4 .301 x height in metres - age x 0.029 - 2.492
The residual standard deviation for this regression equation is 0.51 Litres. So for a subject aged 45 yrs of height 1.87 metres who records an FEV1 of 3.653 Litres his predicted is given by:
Predicted FEV1 = 4.301 x 1.87 - 45 x 0 .029 - 2.492
That is 8.043 - 1.305 - 2.492 = 4.246 litres
This man's recording is (3.653 - 4.246) / 0.51 standardised residuals from predicted, which equals - 1.186 SR from predicted. If we accept 1.645 SR below predicted as defining the LLN this result is within the normal range.
Why is the LLN set at 1.645 SR below predicted?
The Figure to the right shows a plot of the FEV1 values from a sample population of normal men of the same age and height with the average value found being 3.5 L and the standard deviation of the spread of results is 0.5 L. For a subject with FEV1 of 2.678 L this is 1.645 SD below the predicted mean, that is 3.5 L minus (1.645 x 0.5), and means that 5% of the normal population have FEV1 values lower than this. The grey shaded area in the graph is 5% of the total area under the graph.
How does GOLD define the presence of airflow limitation?
GOLD applies a value of 70% for the value of FEV1 as a percent of FVC to define airflow limitation. All major prediction equations find that FEV1% falls with age and so the LLN for this index also drops with age. The Figure opposite shows a theoretical sample population of men whose data fit the NHANES III [ 12 ] equation for FEV1%. All subjects plotted as green dots are truly within the normal range. Those plotted in red are below the LLN and represent the expected 5% of the total population (vide supra). The light blue dots are those subjects where GOLD falsely says they are normal (>70%) but are in fact below the LLN (false negatives) and the mid blue dots are those where GOLD says they are abnormal when in fact they are above the LLN (false positives).
When considering a similar plot for females in the Figure opposite it can be seen that the age at which the 70% cutoff changes from giving false negatives (light blue) to false positives (mid blue) in women is about 50 yrs and is older than that found in men, approx 40 yrs.
Thus not only does the GOLD criterion of <70% for FEV1% falsely categorise subjects it also introduces a sex bias.
To the right is the same plot as above but for females, and it can be seen that the age where false positives start is again older in the females, and now there are some subjects that GOLD says are normal (light blue dots) but who are in fact below the LLN and so are false negatives.
The GOLD criteria were set up in 1997 in an attempt to standardise the future research into COPD so that all workers in the field could work to a common standard. There was insufficient evidence at the time to substantiate the rules that were presented. In the light of current evidence it is clear that the main crux of diagnosis of COPD by the GOLD criteria are flawed.
This will lead to more older subjects being diagnosed with COPD than is justified, since the inclusion criteria as shown above will include a significant number of normal subjects who do not have disease, as well as lead to false negative findings in younger subjects [ 5-11 ]. These false positives will then possibly receive treatment and unnecessary tests they do not require and bear the burden of the label of disease they do not warrant.
It is clear that the scientific community in Respiratory Medicine move to correct this anomaly so that research into COPD is not contaminated by the rules being wrong at the start.
Added Sept. 10, 2009:
The GOLD Guidelines , which originally recommended a FEV1/FVC ratio below 0.70 as indicative of obstructive lung disease, now state:
“…because the process of aging does affect lung volumes the use of a fixed ratio may result in over diagnosis of COPD in the elderly, especially of mild disease. Using the lower limit of normal (LLN) values for FEV1/FVC, that are based on the normal distribution and classify the bottom 5% of the healthy population as abnormal, is one way to minimize the potential misclassification”.
In keeping with the ATS and ERS recommendations, in order to avoid over diagnosing (and therefore over treating) elderly patients, and under diagnosing younger patients, the GOLD guidelines state that:
“…many experts recommend use of the lower limit of normal for each population”.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management and Prevention of
COPD. GOLD, 2007. Available from: www.goldcopd.org
- Kerstjens HAM. The GOLD classification has not advanced understanding of COPD. Am J Resp Crit Care Med 2004; 170: 212-213.
- National Institute for Health and Clinical Excellence (NICE). Summary of key priorities for implementation, algorithms and audit criteria. Thorax 2004; 59: 19-26.
- Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26: 948-968.
- Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, Mørkve O. Risk of over-diagnosis of COPD in asymptomatic elderly never smokers. Eur Respir J 2002; 20: 1117-1122.
- Hnizdo E, Glindmeyer HW, Petsonk EL, Enright P, Buist AS. Case definitions for chronic obstructive pulmonary disease. COPD: Journal of Chronic Obstructive Pulmonary Disease 2006; 3: 1–6.
- Celli BR, Halbert RJ, Isonaka S, Schau B. Population impact of different definitions of airway obstruction. Eur Respir J 2003; 22: 268–273.
- Aggarwal AN, Gupta D, Behera D, K Jindal SK. Comparison of fixed percentage method and Lower Confidence Limits for defining limits of normality for interpretation of spirometry. Respir Care 2006; 51: 737–743.
- Culver BH. We can do better than the GOLD standard. Respir Care 2006; 51: 719-721.
- Roberts SD, Farber MO, Knox KS, Phillips GS, Bhatt NY, Mastronarde JG, Wood KL. FEV1/FVC ratio of 70% misclassifies patients with obstruction at the extremes of age. Chest 2006; 130: 200–206.
- Quanjer PhH, Tammeling GJ, Cotes JE, et al. Lung volume and forced ventilatory flows. Report Working Party Standardization of lung function tests; Official Statement European Respiratory Society. Eur Respir J 1993; 6 Suppl 16: 15-40.
- Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999; 159: 179-187.
Additional references that advocate the use of the lower limit of normal and/or reject a fixed FEV1/FVC ratio
- Miller MR, Pincock AC. Predicted values: how should we use them? Thorax 1988; 43: 265-267.
- ATS Statement. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 144: 1202-1218.
- Viegi G, Pedreschi M, Pistelli F, et al. Prevalence of airways obstruction in a general population. European Respiratory Society vs. American Thoracic Society definition. Chest 2000; 117: 339S-345S,
- Enright PL. Are six seconds long enough? Prim Care Respir J 2006 Oct;15(5): 268-70
- Schermer TRJ, Quanjer PH. COPD screening in primary care: who is sick? Prim Care Respir J 2007; 16: 49-53.
- Hansen JE, Sun X-G, Wasserman K. Spirometric criteria for airway obstruction. Use percentage of FEV1/FVC ratio below the fifth percentile, not < 70%. Chest 2007; 131: 349-355
- van den Berg JWK, van der Molen T, Kerstjens HAM, Quanjer PH. Kanttekeningen bij screenend longfunctieonderzoek voor detectie van COPD. Ned Tijdschr Geneeskd 2007; 151: 1557-1560 (in Dutch).
- Miller MR et al. Defining the Lower Limit of Normal for FEV1/ FVC. Letter to the Editor. Am J Resp Crit Care Med 2007; 176: 101-102.
- Enright P, Quanjer P. Don't diagnose mild COPD without confirming airway obstruction after an inhaled bronchodilator. Editorial. COPD 2007; 4: 89-90.
- Townsend MC. Conflicting definitions of airways obstruction: drawing the line between normal and abnormal. Chest 2007; 131: 335-336
- Shirtcliffe P, Weatherall M, Marsh S, et al. COPD prevalence in a random population survey: a matter of definition. Eur Respir J 2007; 30: 232–239
- Enright P, Quanjer P. Spirometry for COPD is both under-utilized and over-utilized. Invited Editorial. Chest 2007, 132: 368-370.
- Falaschetti E, et al. Diagnosis of COPD. Letter to the Editor. Thorax 2007, 62: 924-925.
- Quanjer PH, Schouten JP, Miller MR, Ruppel G, et al. Avoiding Bias in the Annualized Rate of Change of FEV1. Letter to the Editor. Am J Respir Crit Care Med 2007, 175: 291-292.
- Schermer TRJ, Quanjer PH. Opsporen van COPD in de huisartsenpraktijk: wie is er eigenlijk ziek? Huisarts & Wetenschap 2007; 50: 385-389 (in Dutch).
- Enright PL. GOLD stage I is not a COPD risk factor. Letter to the Editor. Thorax 2007; 62: 1107.
- Miller MR. What defines abnormal lung function? Letter to the Editor. Thorax 2007; 62: 1107.
- Petsonk EL, Eva Hnizdo E, Attfield M. Definition of COPD GOLD stage I. Letter to the Editor. Thorax 2007 ;62: 1107-1108.
- Roberts SD, Farber MO, Knox KS, et al. FEV1/FVC ratio of 70% misclassifies patients with obstruction at the extremes of age. Chest 2006; 130: 200–206.
- Medbø A, Melbye H. Lung function testing in the elderly: can we still use FEV1/FVC <0.70 as a criterion of COPD? Respir Med 2007; 101: 1097–1105.
- Swanney MP, Ruppel G, Enright PL, et al. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax 2008; 63; 1046-1051
- Stanojevic S, Wade A, Stocks J, et al. Reference ranges for spirometry across all ages. A new approach. Am J Respir Crit Care Med 2008; 177: 253–260
- Olofson J, Bake B, Tengelin MN and Houltz B. COPD ‘diagnosis’ based on spirometric reference equations. The Clinical Respiratory Journal 2008; 2: 214–219.
- Schermer TR, Smeele IJ, Thoonen BP, et al. Current clinical guideline definitions for airflow obstruction leads to substantial overdiagnosis of COPD in primary care. Eur Resp J 2008;32(4):945-952.
- Cerveri I, Corsico AG, Accordini, et al. Underestimation of airflow obstruction among young adults using FEV1/FVC, 70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes. Thorax 2008; 63; 1040-1045
- Ko FWS, Woo J, Tam W, C. Lai KW, Ngai J, Kwok T, Hui DSC. Prevalence and risk factors of airflow obstruction in an elderly Chinese population. Eur Respir J 2008; 32:1472-1478.
- Lau AC, Ip MS, Lai CK, Choo KL, Tang KS, Yam LY, Chan-Yeung M. Variability of the prevalence of undiagnosed airflow obstruction in smokers using different diagnostic criteria. Chest 2008; 133 (1): 42-48.
- Levy ML, Quanjer PH, Booker R, Cooper BG, Holmes S, Small I. Diagnostic Spirometry in Primary Care: Proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendations. Prim Care Resp J 2009; 18(3) 3 September.
- Miller MR,Pedersen OF, Pellegrino R, Brusasco V. Debating the definition of airflow obstruction: time to move on? Editorial. Eur Respir J 2009; 34: 527–528.
- Vollmer WM, Gíslason B, Burney P, et al. Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study. Eur Respir J 2009; 34: 588–597.
- Cerveri I, Corsico AG, Accordini S, et al. What defines airflow obstruction in asthma? Eur Respir J 2009; 34: 568–573.
See also: Expressing test results