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, MD İ.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
Falaschetti ERJ 2004 174cm, male Pred. mean LLN 165cm, female
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)
Usin the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Swanney Thorax 2008 40 646 adult/13 136 asymptomatic and never smoker American (4630)-Dutch (1204)-British (7302) populations’s pirometry data 42age COPD prevalence in asymptomaticandneversmokeradults.HSE: HealthSurveyforEngland 1995-96, NL: Hollanda verisi, NHANES: NationalHelathandNutritionExaminationSurvey (beyaz ırk için Amerika verisi) 48age LLN for FEV1/FVC decreases in healthy population with age (in man 57, in women 55 prediction equations)
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 Swanney Thorax 2008
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 England Nonsmoker 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
GOLD 2006 GOLD 2010 • 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 • Howeverreference equations using post BD FEV1 and longitudinal studies to validate the use of LLN are urgently needen.
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)
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 GOLD Prebd LLN 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-termstudy/mortalityand COPD relatedhospitalisation • 4965 cases (>65 years), 11 years of follow-up • 1134 cases had FEV1/FVC<0.70 but > LLN Mortality (HR 1.3) andhospitalisation (HR 2.6) higherthancaseswith normal spirometry Fixedratiomayidentify at-risk patients. Using LLN toclassifylungdisease in olderpeoplemaymiss a part of thepopulationmorelikelytohavecomplications.
FEV1/FVC LLN Fixed ratio 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 Fixed ratio Ratio LLN GOLD 2-4 LLN and FEV1<%80 Ratio and FEV1 <LLN GOLD 2-4 prevalence NHANES III Local pred equations COPD prevalence in never smoker healthy people
FEV1/FVC<0.70 disadvantages • 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 Underdiagnosis in young adults Delay in treatment
LLN için sıkıntılar Problems of LLN • Needsstatisticalanalysis. New spirometries do this but no print-out. • Changesaccordingtoreferenceequations (Countries/ethnicgroupsneeddifferentreferenceequations/if not, usethemostsuitableone
1995-2004 arası yayınlanan referans denklemleri White people have at least 30 reference equations for FEV1/FVC LLN They must be specific for countries
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?