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Are they really sick?

Predicted valuesfor spirometryfor elderlysubjects, and theconsequencesfor diagnosingCOPD

Tjard Schermer& Philip H. QuanjerNovember 29, 2006

Presentation made at meetingof general practioners in theNetherlands

Are they really sick? 1

December 2, 2006 T Schermer & Ph Quanjer


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When dealing with spirometric data there are certain essential requirementsthat need to be met:

1 Use of appropriate equipment, regular calibration2 Manoeuvres performed correctly3 Quality assessment of data4 Appropriate predicted values

5 Adequate interpretation (including bronchodilator effects)6 If appropriate: classi cation of severity of any abnormality.

Standardising a number of aspects of lung function testing was rst undertakenin Europe in 1960 by the European Community for Coal and Steel, a branch ofindustry with a high prevalence of disease due to inhaled particles. At regularintervals international bodies in Europe and the USA improved and re nedtheir recommendations and included a wider spectrum of lung function indices.Below is a chronological account of recommendations:

1960 - Jouasset D. Normalisation des preuves fonctionnellesrespiratoires dans les pays de la Communaut Europenne duCharbon et de lAcier. Poumon et Coeur 33; 1145-1159.

1971 ECCS Update.1979 - ATS statement - Snowbird workshop on standardization of

spirometry. Am Rev Respir Dis 119: 831-838.1983 - Standardized Lung Function Testing, ECCS. Bull Europ

Physiopath Resp 19, suppl. 5, 5-95.1993 - ECCS-ERS update. Eur Respir J 6, suppl. 16, 5-100.1995 - ATS update. Am J Respir Crit Care Med 152: 1107-1136.2005 - ATS/ERS recommendations. Eur Respir J , series 1-5 ATS/ERS

Task Force: Standardization of Lung Function Testing.

One is inclined to conclude from the above list that all has been attended toby now. However, that is not the case: whereas standards are issued in many

elds, most people just pay lipservice to them. Sadly, supervising spirometrictests in clinical surveys shows that the quality and adherence to internationalguidelines often leaves something to be desired. Among the errors mostfrequently encountered are:

No blast at start of the manoeuvre

Premature end of manoeuvreCoughOnly one or two manoeuvresInspiration not to TLCUnsatisfactory reproducibilitySelected FEV 1 and FVC not the largest of

3 manoeuvresNo calibration or linearity check of

equipment

Premature end of manoeuvre




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No blast at start manoeuvre.

No blast at start manoeuvre andno maximal effort.

Poor cooperation, no reproducible

results.

It is more or less obvious how this condition can be improved; we will deal withthat later.

At the start of this century a number of people, the GOLD group, with thesupport of most if not all large pharmaceutical companies, addressed theproblem of underdiagnosis of COPD. Their objective was to improve thediagnosis and increase awareness of underdiagnosis. They felt that establishing




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the true lower limits of normal for spirometric indices was too complicated forpracticing physicians; they therefore introduced a very simple rule: if FEV 1 %VCafter bronchodilatation is less than 70% this signi es airway obstruction,in fact COPD. They also provided guidance how to classify the severity ofairway obstruction (table on previous page, GOLD recommendations 2004,see www.goldcopd.com ). COPD is therefore a laboratory nding, similar to

hypertension or anemia. The GOLD committee does not claim that any of itsrecommendations is evidence based.

The GOLD guidelines quickly gave rise to a ourishing literature on COPD whichled to the conclusion that the prevalence of COPD was even larger than hithertosuspected. This led to a threatening scenario of excessive rise in the burden ofdisease due to the ever increasing proportion of elderly and aged people in thepopulation, so that the cost of healthcare would explode. Medical organisationsworldwide were alarmed, adopted the GOLD guidelines, tried to take measuresso as to identify and treat subjects with COPD at an earlier stage, and thus

potentially stem the tide.Obviously Dutch general practitioners form part of this worldwide communityand are prepared to make their contribution. In this document we will try toanswer the question to what extent support for the GOLD guidelines can beretrieved from the literature and large databases. In doing so we focus on:

1 Is FEV 1 %VC < 70% a valid index of the presence of airway obstruction?2 Is the use of FEV 1%predicted a valid index to assess the severity of airway

obstruction?3 How large are differences in published predicted values for various

spirometric indices, and to what extent do they affect the evaluation ofspirometric data in diagnosing COPD, as well as the severity of airwayobstruction?

Is FEV1%VC < 70% a valid index of the presence of airwayobstruction?The Falling Ratio WorkingGroup, an international groupof investigators, retrievedfrom the international

literature about 45 publications on FEV 1%FVC and itslower limit of normal (LLN).In most of these publicationsthe prediction equation forFEV1 %VC is of the form:

Y = a + bAge + cHeight

and provides guidance how

to compute the LLN. The twographs (this and next page)show FEV 1 %VC for white men


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and women as a functionof a population of averageheight. With few exceptionsthe FEV 1 %VC, computed inkeeping with the publication,falls well below 70%. It is

also obvious that airwayobstruction will be frequentlyoverlooked in young adultsif the 70% GOLD criterion isapplied.

Conclusion 1

The GOLD criterion for establishing airway obstructionis de nitely not suitable for

indiscriminate application toany population, as it will beassociated with false negativeresults in young adults, and with false positives in older adults.

How does the 70% cut-off perform in a healthy reference population (negativerespiratory history, lifelong nonsmoker)? Assuming that the author has properlyde ned the LLN, then convention has it that 5% of a reference population


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may produce a result below that LLN. In the example on the previous page.comprising 2269 healthy nonsmoking English men, this is indeed the case:5.24% prevalence of airway obstruction. The LLN is therefore appropriate forthis population (Falaschetti et al. Eur Respir J 2004; 23: 456-463). In a random sample of the population the 70% GOLD criterion, whichneglects the age and height dependence of the LLN, produces false negative

(blue) and false positive results (red). Just to clarify: if only the authors criteria(LLN) had been applied, then the blue circles would have been green (belowthe LLN) and the red ones would have been black (above the LLN). The LLN istherefore just above the blue and below the red circles.

It is unlikely that a GP will perform spirometry on subjects without any likelihoodof lung disease. What are the ndings in a random sample of the population inEngland, hence including subjects with respiratory disease?

The picture is essentially the same. The prevalence of airway obstruction hasdoubled, 13.2%. A nice feature of a higher prevalence is that the percentageof false positives drops. The predictive value of a positive test has increased byonly a small amount.

The above population is more representative of the people seen in a GPs of ce.

What about patients seen at a hospitals clinical and outpatient departments?Those are the patients the GP has referred to the chest physician. Theillustration on the next page shows the ndings in 2393 patients at Dijkzigt




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Academic Hospital, Rotterdam. The prevalence, and the predictive value of apositive rest result, is higher again. Needless to say that the larger the a priori likelihood of the presence of airway obstruction, such as in this selected patientpopulation, the smaller the percentage of false positives. We shall see shortlythat this statement has to be taken with a grain of salt .

Using the GOLD guidelines it is not possible to classify all subjects. In a largeDutch population study (Vlaardingen-Vlagtwedde) 5.70% of subjects could notbe classi ed. Khler et al . ( Thorax 2003; 58: 825) could not classify 10% of1,000 patients clinically treated for COPD; previous recommendations of ERSand ATS did not lead to this problem, the authors found.

What if I apply a set ofprediction equations that hasnot been derived from the




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population I am going to apply them to? The above gure illustrates ndingsin 2406 Dutch males, a random sample from the population. The blue line represents the LLN according to ECCS/ERS. If we would slightly elevate the levelof the LLN, for example as high as the yellow line, this would obviously increasethe number of false negatives and decrease the number of false positives. At this stage the predicted values due to Hankinson are widely used in theUnited States ( Am J Respir Crit Care Med 1999; 159: 179-187). The predictedvalue for the LLN for FEV 1%FVC is only slightly higher than that of ECCS/ERS.How does substitution of Hankinsons equations work out in Dutch men andwomen?

Predicted value ECCS HankinsonMan Women Man Women

Increase positives +16.6% +16.6%FP%pos 31.6% 42.3% 17.9% 10.6%FN%neg 0.0% 0.3% 3.2% 5.8%

FN = false negative, FP = false positive

In spite of the rather small change in the LLN the number of people identi edas having airway obstruction with Hankinsons prediction equation increases by

1/6, and accordingly the percentage of false positives diminishes. Obviouslythe trend is reversed with regard to false negatives. It is therefore useful tohave a closer look at the comparibility of predicted values and how differenceswill affect your decisions.


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In previous text and illustrations we displayed falsenegatives as a % of all negative test results, and falsepositives similarly as a % ofall positive test results. That

is not ef cient. After all, falsenegatives are limited to theyounger adults, and falsepositives to the older ones.The latter is usually regardedas the target group in thecase of COPD. It is therefore moreuseful to use age-speci cpercentages. This was done

in the illustration on the rightfor the large NHANES IIIpopulation. Subjects werecentered by age; thus age50 means that persons wereaged between 47.5 and 52.5year.The message is quite bewildering: above age 55 or 60year the GOLD criterion leadsto doubling the prevalence ofairway obstruction (COPD).Hence for individuals in thisage range in whom airwayobstruction is diagnosedbecause FEV1%FVC < 70%, in about 50% of cases this is scienti callyuntenable. In particular the GOLD guidelines have been responsible for alarmistmessages about the high prevalence of COPD in the population, and the futureincrease in the burden of disease because ever more people tend to grow older.Indeed the gure shows (red columns) an upward trend in the point prevalence

of airway obstruction with age, and the percentages for age cohorts are indeedhigh, but the by and large equal percentage of false positive ndings should infact be added to the true negatives. These ndings relate to a random sample of the American population.However, random samples from an English and Dutch population lead to quitesimilar ndings.

Conclusion 2 .There surely is an upward trend with age in the prevalence of airway obstruction,but from age 50 in men, and age 60 in women, the prevalence is arti cially

doubled because the GOLD guideline fails to take into account that FEV 1%FVCvaries with both age and standing height.As the GOLD criterion: FEV 1%FVC < 70% = airway obstruction (= COPD)

leads to excessive errors, this criterion is untenable.




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Grading the severity of airway obstruction is conventionally based onFEV1%pred. The use of this index for clinical purposes is standard practice. Beingsanctioned by use, is there any problem? Well, think about this. No author ofpredicted values has ever recommended to express FEV 1 as a percentage of thepredicted value for whatever evaluation of spirometric test results. Similarly nostandardisation group has ever made such a recommendation. On the contrary,

just like authors of predicted values such committees recommend to computethe LLN of FEV 1 (and FVC, and other indices) lege artis , i.e . using appropriateand standard statistical techniques. Doconsult:

ATS Statement. Lung function testing:selection of reference values andinterpretative strategies. Am Rev RespirDis 1991; 144: 1202-1218.

Quanjer PhH, Tammeling GJ, Cotes JE,Pedersen OF, Peslin R, Yernault JC. Lung

volumes and forced ventilatory ows. EurRespir J 1993; 6 suppl. 16: 5-40. (ECCS/ERS statement).

Pellegrino R, Viegi G, Brusasco V, Crapo RO,Burgos F, et al. Interpretative strategiesfor lung function tests. Eur Respir J 2005;26: 948-968. (ATS/ERS statement).

So what is wrong, and what are theconsequences? Do please look at thegraph on the right. It shows for men

of 1.90 m height, and for small men of 1.65 m height, how according tothe ECCS/ERS prediction equations FEV 1 relates to age. Extending from thepredicted value is a colored zone ending in red. The lower border of that zonerepresents the lower limit of normal, the 5 percentile: below that zone is 5%of a healthy non-smoking population from whom the equation was derived.The yellow interrupted line represents 80% of the predicted value. The smallerthe predicted FEV 1 , the closer the line gets to the predicted value. The use ofpercentages is correct if the scatter about the predicted value is proportional tothat value, so that the scatter becomes smaller as the predicted value becomessmaller. But that is not what is experimentally observed, however contra-intuitive this may be. The graph shows clearly that the use of % predicted leadsto an important age and height related bias. The proportion of false positive

ndings increases with age, with diminishing height, and is particularly largeif people are both small and aged. We know that older generations were notas tall when they were young as younger generations, and that the ageingprocess is associated with diminishing standing height, so that both factors willaggravate the age-related bias.

Conclusion 3 .The use of % predicted leads to false positive ndings at an older age, in smallpeople, and especially in elderly small people. Use of percentage predicted hasbeen sanctioned by usage, but its use is limited to the domain of lung diseases.One cannot complain that there are no publications on how to properly computethe LLN, but apparently this is not the literature favored by clinicians.




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What then is the proper way to establish the LLN? Let us consider anexample.The illustration below depicts the FEV 1 obtained in 832 Dutch

women who never had chronic respiratory symptoms and who were lifelongnonsmokers. The scatter about the mean (SD) comes to 610 mL. Differences inFEV1 between subjects are due in part to differences in standing height and inage. By performing regression of FEV 1 on height and age we can establish therelationship and explain part of the differences. If we now use the equationwe derived to correct measured values for differences in age and height youobtain the illustration on the right. The SD of FEV 1 is now 477 mL, it decreasedby 22%. The remaining scatter is called residual scatter, a measure of which isthe residual standard deviation (RSD).

The equation we derive is of the following form:

FEV1 = a + bHeight + cAge +

= residual standard deviation (RSD)

When using %pred we want to know how far the observed value is removed (in%) from the predicted one. Similarly we wish to establish how many RSD themeasured value differs from the predicted one.

If the residual scatter is normally distributed the LLN is at:predicted 1.645RSD

In the case of 80% predicted we (incorrectly) assume that the LLN is 20%below the predicted value. However, the appropriate index is to compute howmany times the RSD the measured value differs from the predicted one, andwe call the result the standard deviation score (SDS), also called z-score orstandardized residual. For normal distributions the LLN is at SDS = -1.645.

Computing the SDS is therefore a simple matter:

SDS = (observed predicted)/RSD




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Interpreting the SDS is an easy matter.

SDSobserved = predicted 0FEV1 at 5 percentile -1.645FEV1 at 2 percentile -1.96

If the author has not indicated a different way to de ne the LLN, one can useSDS = -1.645 as the 5 percentile for any index in children and adults, men andwomen. Or SDS = -1.96 as the 2 percentile.

Which prediction equations t a Dutch population ? The predictionequations almost universally used in Europe are those due to ECCS/ERS. If weapply these to a representative sample of the Dutch population (no symptoms,lifelong nonsmokers), this is what we nd (in liters):

FEV1 FEV1-predicted FVC FVC-predictedWomen 2.06 0.22 3.71 0.52

Men 4.49 0.30 5.65 0.60

Predicted values, except those for FEV 1%VC, aretoo low. But this can be redressed by applyingthe corrections in the table on the left.

Comparison of the ECCS/ERSprediction equations withother ones discloses that theECCS values are low; this hasindeed been documented in anumber of publications. After

the above corrections thepredicted values t a healthyDutch population. The gureon the right shows predictedvalues for women and menof average height, age 60year; the adjusted ECCS/ERS predicted values are nowin line with a series of otherpredicted values.

Index Gender Correc-tion

FEV1 women + 8%FEV1 men + 8%FVC women + 15%

FVC men + 10%




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What is a valid age range for ECCS/ERS predicted values?Below is a quotation from the original ECCS publication (1983, p. 50):

The summary equations were derived for an age range of 25-70 years,and for a height range of 1.55-1.95 m in men, and 1.45-1.80 m in women.According to various sources predicted mean values in cross-sectional

studies do not decline with age between 18-25 years of age, so that theyare the same as for a subject aged 25 years. For subjects older than 70years, and for subjects outside the above height ranges, it is permissibleto obtain predicted mean values by extrapolation from the regressionequations.

The prediction equations were not changed in the 1993 ECCS/ERS update. Thetwo graphs below (FEV 1 uncorrected for differences in height) show that indeedno harm is done in extending the valid age range to 80 yr. Obviously thisstill leaves thecorrection,alluded to onthe previouspage, to beattended to.




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What replaces % predicted?The severity of airway obstruction is conventionally gauged from FEV 1%pred.But that index is biased by age and standing height and should, as explained,be abandoned in favor of the z-score (SDS). If we wish to maintain the arbitraryGOLD stages we must nd a way to de ne limits that closely t the ones de nedby the GOLD group. This can be done by regressing FEV 1%pred on SDS, or the

other way around. In over 16,000 measurements in de NHANES III study thisgives rise to the following relationship:

SDS = -6.880 + 0.0686FEV 1%pred

Correlation 0.977, RSD 0.20. Substitution gives rise to the following table:

FEV1%FVC FEV 1Obstruction % SDS %voorspeld SDS none >70 >-1.645 mild -1.645

moderate


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Few people like change. So they usually object that these computations areunnecessarily complex. But that is not true. To compute %pred a division needsto be performed, just as in the case of the SDS; it is true that one also needs toknow the RSD of the prediction equation. But is there any doctor who performsthese computations himself? Of course not, it is all presented by computer, sowhy worry about the computational aspects?

What happens to the severity grading if we replace %pred with the SDS? Thegure below illustrates this for the large NHANES III population. The numbers

1-4 in the left gure represent the staging according to GOLD guidelines. Onthe right is the equivalent staging using the LLN and SDS. The number ofpeople with airway obstruction falls from 2374 (GOLD) to 2010, i.e . by 15%.That, however, is a super cial conclusion. After all, in younger age groups a fewhundred subjects are erroneously diagnosed as not having airway obstruction

when applying the GOLD criterion that FEV 1%VC should be < 70%, and isappropriately identi ed by applying Hankinsons LLN. Furthermore a very largenumber of false positives is correctly staged by using the LLN. So overall there arevery important age-relatedshifts in the assessmentof spirometric data, due

to which mild obstruction(GOLD stage I) becomesmore prevalent, particularlyamong young adults,GOLD II becomes muchrarer, with only minor changes in the severer classes of airway obstruction. TheGOLD guidelines, therefore, give rise to considerable inaccuracies in gradingthe less severe cases of airway obstruction. One can criticise these analyses for the fact that the GOLD guidelinesrequire interpretation of FEV 1%VC after bronchodilatation. None of the data

presented comply with that requirement. However, according to a recentstudy by Johannessen et al . ( Thorax 2005; 60: 842-847) this would reducethe prevalence of airway obstruction based on GOLD criteria by only 27%,

GOLD stage GOLD method LLN-SDS method I 1194 1490

II 933 261III 242 216IV 35 43Total 2374 2010




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which falls far short of reducing the gross overestimate of airway obstructiondemonstrated in this manuscript. But apart from that, we are not aware of anyevidence that an FEV 1%VC ratio < 70% either prior to or after bronchodilatation implies airway obstruction, or COPD. It is in addition a rather peculiarrequirement. Must we really expose a population regarded as healthy tobronchodilator drugs? If the answer is af rmative, can we only arrive at the LLN

for blood pressure in healthy people after administration of a drug that affectsblood pressure and administration of a diuretic drug? Should we establish theLLN for the hemoglobin concentration in healthy subjects after administeringsupplementary vitamin B 12 , folic acid and iron?

This gives rise to the following conclusions and recommendations with regardto measurement requirements, and the interpretation of measurements:

Essential basic conditions :1 Use appropriate equipment, regularly tested and calibrated. Generally few spirometers are sold with equipment (calibration syringe)

required for checking linearity and calibrating output. Draw up a list ofsuitable hardware AND software.

2 Adhere to minimal requirements that have been internationally recommended.

Quality assessment during intervention studies reveals that frequentlyquality of spirometry is unsatisfactory. The following measures are suitablefor making it dif cult to neglect internationally accepted standards:

3 Quality control online, immediate feedback, via software. Apply the ATS/ERS ( Eur Respir J 2005; 26:319-338) or NLHEP criteria

(see footnote). Draw up a list of minimal requirements that software

should comply with and inform dealers that henceforth only equipmentand associated software that is on that list will be recommended togeneral practitioners.

4 Store quality assessment with the data. Thus it will always be clear how much weight should be attached to

a measurement on le. It will not always be possible for a patient tocomply completely ( e.g . in the case of mental limitations, poor hearing,paralysis, pain, etc.). There is no reason to reject the good with the bad,as sometimes the measurements may yield clinically useful informationeven though they do not meet quality criteria.

5 Certify personnel and laboratories. Inevitable, because correctly administering spirometry is not easy, cannotbe done casually, and requires professional training and maintenance ofgood laboratory practice, as well as postgraduate training. It should bepossible to achieve this through cooperation with the national societies ofchest physicians and lung function technicians.

6 Certi cation of laboratories to be periodically renewed. Certi cation for an inde nite period is not acceptable. The system will

probably entail site visits.7 Resolve the issue of predicted values and their lower limits of normal.

This is an international challenge, important for daily medical practice.8 Sick: FEV 1 , (F)VC, FEV 1%(F)VC: Forget about the rest.

http://www.nlhep.org/resources-medical.html#review, click on Of ce Spirometry for Lung HealthAssessment in Adults - A Consensus Statement from the NLHEP




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Spirometric tests give rise to a plethora of indices. They have no addedvalue above the above.

9 Who is ill? Do not treat laboratory ndings. Illness is a clinical condition.10 When are pharmaceutical interventions appropriate? Unfortunately the literature is not encouraging. Apart from smoking ces-

sation it seems that so far COPD eludes medical intervention, except tosome extent in the severest stages. That underlines the necessity to onlyperform spirometric tests if there is prior evidence of respiratory dis-ease.

The combination of recommendations 1-5 will be invaluable in improving thequality of spirometric tests if general practitioners learn to take due account ofthem when evaluating the patients condition.

Interpretation of spirometric data :1 The GOLD criterion FEV 1%VC < 70% leads to gross overestimates in the

prevalence of airway obstruction in people over age 50 yr because it isassociated with a pronounced age and height bias. This in turn leads tovery signi cant over-diagnosis of COPD in this age range.

2 The same criterion is responsible for under-diagnosis of airway obstructionin young adults.

3 FEV 1%predicted similarly leads to a height and age bias. Arising fromthis the severity of airway obstruction is systematically overestimated inelderly and small subjects.

4 All published research and recommendations issued by expert committeesrecommend to use the lower limit of normal, none recommend the useof % predicted.

5 A scale is presented in which %pred is replaced by standard deviationscore, allowing to assess the severity of airway obstruction in a scienti callycorrect manner.

If people wish to adhere to the four GOLD stages there will always bea signi cant proportion of subjects whose measurements cannot beclassi ed, i.e. in those who have no airway obstruction (FEV 1%FVC >LLN) but FEV 1 < LLN. Each scaling system has so far been arbitrary, andmuch more research is required to establish to what extent pulmonaryfunction data are prognostic of increased morbidity and premature death,allowing the construction of a validated scale.




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It was six men of IndostanTo learning much inclined,

Who went to see the Elephant(Though all of them were blind),

That each by observationMight satisfy his mind.

The FIRST approached the Elephant,And happening to fall

Against his broad and sturdy side,At once began to bawl:

God bless me! but the Elephant Is very like a wall !

The SECOND, feeling of the tusk,Cried, Ho! what have we here

So very round and smooth and sharp? To me tis mighty clear

This wonder of an Elephant Is very like a spear !

The THIRD approached the animal,And happening to take

The squirming trunk within his hands,Thus boldly up and spake:

I see , quoth he, the Elephant Is very like a snake !

The FOURTH reached out an eager handAnd felt about the knee,

What most this wondrous beast is likeIs mighty plain , said he:

Tis clear enough the Elephant Is very like a tree !

The FIFTH, who chanced to touch the ear,Said: Een the blindest manCan tell what this resembles most;Deny the fact who can,This marvel of an Elephant Is very like a fan !

The SIXTH no sooner had begunAbout the beast to grope,Then, seizing on the swinging tailThat fell within his scope,

I see , quoth he, the Elephant Is very like a rope !

And so these men of IndostanDisputed loud and long,Each in his own opinionExceeding stiff and strong,Though each was partly in the right,And all were in the wrong!

Moral

So oft in scienti c warsThe disputants, I ween,Rail on in utter ignoranceOf what each other mean,And prate about an elephantNot one of them has seen!

John Godfrey Saxe

Finally : It is a crucial problem that we do not know how tode ne COPD. The general pattern of reasoning is more or lessas follows: Grass is green. Cows eat grass. Hence cows are green.In the context of COPD: COPD is associated with airwayobstruction. Therefore airway obstruction is COPD. The

medical profession has agreed that airway obstruction inCOPD is typically hardly responsive to bronchodilator drugs.Hence irreversible airway obstruction is COPD.Free translation: we have little understanding of the natureof COPD, hardly comprehend what it is, everyone has seenit and has therefore formed an opinion about it. That is whatthe following poem is about.

The Blind Men and the Elephant


are they really sick?

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