Conflict of Interest

Actelion, Bohringer-Ingelheim, Bayer (Congress support and study)

LFT parameters used in COPD diagnosis and their role in clinical practice: Lower Limit of Normal

Esen KIYAN, MDİ.Ü. İstanbul Medical Faculty

Department of Respiratory Diseases

LLN: statistical definition

Below 5th percentile of reference population (false negative rate %5)

FEV1, FEV1/FVC depends on age, gender, height and race.

Hankinson JL, AJRCCM 1999

174cm, male

165cm, female

Falaschetti ERJ 2004

Pred. mean

LLN

Fixed ratio fits all ?

In healty people, decrease in FEV1 with age is bigger than decrease in FVC. This causes decrease in FEV1/FVC ratio by age.Age>45, LLN for FEV1/FVC<0.70

(Falaschetti E, ERJ 2004; Stanojevic S, AJRCCM;2008; Stanojevic S, ERJ 2010)

Obstruction= FEV1/FVC<LLN (<5th percentile of predicted value, 5th percentile of healthy population)

LLN=predicted value – (1.645*SD)

LLN for FEV1/FVC decreases in healthy population with age (in man 57, in women 55 prediction equations)

40 646 adult/13 136 asymptomatic and never smokerAmerican (4630)-Dutch (1204)-British (7302) populations’s pirometry data

Usin the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Swanney Thorax 2008

COPD prevalence in asymptomatic and never smoker adults. HSE: Health Survey for England 1995-96, NL: Hollanda verisi, NHANES: National Helath and Nutrition Examination Survey (beyaz ırk için Amerika verisi)

42age

48age

Swanney Thorax 2008

COPD prevalence in men and women according to GOLD and LLN definition

False COPD diagnosis in healthy adults over 60 years: %17-45 in men, %7-26 in women

Fixed raio causes high (50%) false positive diagnosis in adults ≥45

Hardie JA, ERJ 2002; Celli BR, ERJ 2003; Roberts SD, Chest 2006; Vollmer WM, ERJ 2009; Swanney MP, Thorax 2008; Ko FWS, ERJ 2008; Schermer TR, ERJ 2008; Miller MR, Chesy 2010; Vaz Fragoso CA, AJRCCM 2010

FEV1/FVC and FEV1 pred values (Falaschetti et al.)1995-1996 Health Surveys for EnglandNonsmoker men without asthma,

At 47 age, LLN for FEV1/FVC<0.7 line (false positive)47-49 ages LLN for FEV1>%80 pred (GOLD stage 1/milfd obst.)Over 50, LLN for<%80 pred (GOLD stage 2/moderate obst.)

GOLD0 criteria misses COPD cases in young adults and therefore causes delay in treatment to prevent disease progression

Cerveri 2009: Age<52, true COPD diagnosis with fixed ratio is 77% in women and 57% in men.Hansen 2007: false negative diagnosis is 50% with fixed ratio

• Since progress of aging affect lung volume, use of fixed ratio may result in overdiagnosis of COPD in elderly, and underdiagnosis in young adults (<45year) (Cerveri I, Thorax 2008).

• Using LLN for FEV1/FVCis one way to minimize potential misclassificaton.

• If reference equations for LLN available, most of the spirometers do this calculation

• However reference equations using post BD FEV1 and longitudinal studies to validate the use of LLN are urgently needen.

GOLD 2006 GOLD 2010

Factors affecting COPD prevalence

• Criteria used for obstruction? Fixed ratio vs LLN?

• Postbronchodilator LFT? • PostBD causes 30% decrease in COPD prevalence

(Johannessen A. Implication of reversibility testing on prevalence and risk factors for chronic obstructive pulmonary disease: a community study. Thorax 2005)

• Which reference equations used?

LLN vs FEV1/FVC<0.70, Which one is correct for COPD diagnosis?

Hoesein M, et al. Lower limit of normal or FEV1/FVC<0.70 in diagnosing COPD: An evidence-based review. Respir Med 2011.MEDLINE, EMBASE, Cochrane data

Studies between 1966-2010

Total 1954 studies……………18 evaluated

Level of evidence (1a/b---expert opinion:5)

Hoesein M, Resp Med 2011

Postbronchodilator LLN for FEV1/FVC causes

further decrease in COPD prevalence.

PostBD FEV1/FVC<LLN and postBD FEV1/FVC<0.70

• Prevalence and risk factors of airflow obstruction in an elderly Chinese population. Ko FWS, ERJ 2008– 1008 people (≥60yaş), LLN prevalence %12.4 vs %25.9

• COPD prevalence in a random population survey: a matter of definition,Shirtclffe P, ERJ 2007– 749 people (≥40 years; 0nly 38.9% was ≥60years), LLN

prevalence %9 vs %14.2

PostBD FEV1/FVC<0.70 vs postBD FEV1/FVC<LLN

• Shirtcliffe P, ERJ 2007 (3500 people/ New Zealand)

• 749 spirometry/ population based/ over 40 years

• Postbd LLN prevalence %9.5 (caused 30% decrease in prebd LLN diagnosis) vs %14.2

• Prebd LLN prevalence %15.2,

• Doctor diagnosis prevalence %10.5

Prebd LLN

GOLD

Doctor diagnosis

Postbd LLN

COPD prevalence according to diagnostic criteria

PostBD FEV1/FVC<0.70 vs postBD FEV1/FVC<LLN

• Lamprecht B, Pulmonary Med 2011• NHANES III reference equations• 1258 correct spirometry • Prevalence with fixed raion 24.2%, with LLN 15.3%, doctor

diagnosis prevalence 5.6%

>LLN but <0.70 (in-between obstruction) group had higher comorbidity-especially cardiac.

Mannino (Cohort study of Cardiovascular Health Study), Thorax 2007

• Long-term study/mortality and COPD related hospitalisation• 4965 cases (>65 years), 11 years of follow-up• 1134 cases had FEV1/FVC<0.70 but > LLN

Mortality (HR 1.3) and hospitalisation (HR 2.6) higher than cases with normal spirometry

Fixed ratio may identify at-risk patients. Using LLN to classify lung disease in older people may miss a part of the population more likely to have complications.

Fixed ratio FEV1/FVC LLN GOLD 2-4 FEV1/FVC LLN, FEV1<%80

FEV1/FVC<LLN, FEV1<LLN

Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study. Volmer WM, ERJ

2009

COPD prevalence in never smoker healthy people

Fixed ratioRatio LLNGOLD 2-4LLN and FEV1<%80Ratio and FEV1 <LLN GOLD 2-4 prevalence

NHANES III

Local pred equations

Turkey-BOLD study (Kocabas A, 2006)

Overdiagnosis in older people

• Unneccessary treatment(?)……side effects and increase in cost

•Psychological trauma and decrease in helath quality

•False positive COPD cases in clinic studies ….false conclusions

FEV1/FVC<0.70 disadvantages

Underdiagnosis in young adults

Delay in treatment

LLN için sıkıntılarProblems of LLN

• Needs statistical analysis. New spirometries do this but no print-out.

• Changes according to reference equations (Countries/ethnic groups need different reference equations/if not, use the most suitable one

1995-2004 arası yayınlanan referans denklemleri

They must be specific for countries

White people have at least 30 reference equations for FEV1/FVC LLN

There is no statistical evidence for fixed ratio and predicted %

LLN is an statistical definition and decreases misclassifications.

Is it true to use GOLD COPD diagnosis criteri?

SONUÇ

• LLN decreases underdiagnosis in young adults and leads to early treatment.

• LLN decreases overdiagnosis in older people (esp GOLD stage I) and decreases unneccessary treatment and therefore prevents unneccessary treatment-complications and increase in cost.

• Subjects classified as >LLN but <0.70 are more likely to die and to have COPD related hospitalisation during follow-up. LLN miss these patients (Mannino Thorax 2003).

• Longitudinal studies using postbronkodilator values are needed.

• Although there is strong evidence to use LLN for obstruction, it is not a routine in our clinical practice .

• Failure to adaptate it to our daily

practice? prefering easy-simple parameter?