copd represents an important public health challenge that is both treatable and preventable.1 currently , copd is the fourth leading cause of death worldwide and is expected to be the third leading cause of death by 2020.2 despite efforts from the medical community , the centers for disease control ( cdc ) reports that smoking rates in the us have only slightly declined since 1997 from 24.7% to 20.8%.3 with copd prevalence increasing , accurate assessments of copd comorbidities and mortality are needed.425 copd results from the interplay between genetic susceptibility and exposure to environmental stimuli.26 in 1977 , fletcher and peto described the natural history of copd , including its relationship with smoking and decline in forced expiratory volume in 1 second ( fev1).27 since that time , copd has been characterized as a poorly reversible airflow limitation , most often defined by fev1.8 historically , the reduction in fev1 has been used to define the severity of copd and frequently cited as an important predictor of mortality.24 additionally , fev1 is frequently targeted as a clinical endpoint in copd clinical trials.2834 other clinical measurements such as inspiratory capacity ( ic ) , 6-minute walk test ( 6mwt ) , the bode index ( body mass index , airflow obstruction , dyspnea , and exercise ) , and dyspnea questionnaires may have stronger associations with mortality than fev1.7,1216,19,24,3539 several publications have focused on the use of the ic / total lung capacity ( tlc ) ratio , a measure of static lung hyperinflation , which has been shown to be strongly associated with exercise - associated dynamic hyperinflation as well as exercise tolerance.4,8,38,40 additionally , studies evaluating the use of resting ic have also demonstrated a strong association between ic and functional exercise limitation in copd patients.41,42 in 2004 , casanova et al evaluated the role of the ic / tlc ratio , in conjunction with the bode index and fev1.7 their cohort consisted of 689 patients ( 95% male ) with 183 deaths ( 178 males and five females ) with a median follow - up less than 3 years ; their results suggested that when compared to fev1 and the bode index , an ic / tlc ratio of 25% offered the best combined sensitivity and specificity for predicting all - cause mortality in copd patients.7 we hypothesize that the ic / tlc ratio is associated with risk of death , when used to evaluate a large cohort over an extended period of follow - up and could be a useful clinical tool in assessing patients with an emphysematous phenotype of copd . we performed a retrospective analysis of a large pulmonary function ( pf ) database , consisting of 39,050 entries , from our institution , which encompasses a broad patient population of inpatients and outpatients from april 1978 to october 2009 . cedars - sinai medical center institutional review board approval ( pro-00012916 ) was obtained for the study . we defined copd patients with an emphysematous phenotype as those with a reduced fev1/fvc ratio , increased tlc , and reduced diffusing capacity of the lungs for carbon monoxide ( dlco ; all beyond 95% confidence intervals ) using established normal values.4244 if the same patient had multiple pf studies , only the first recorded pf was included in the study analysis . lastly , patients were excluded if they were under the age of 18 years . using the social security national death index ( ssndi ) , we established absolute dates of death . if the subject did not have a reported date of death in the ssndi , they were assumed to be alive 8 weeks prior to the date that the ssndi was queried . univariate analysis was completed to evaluate the relationship between ic / tlc ratio and survival . additionally , disease severity was graded using the fev1 as defined by the global initiative for chronic obstructive lung disease ( gold ) criteria.46 body mass index ( bmi ) was treated as ordered categories ( bmi : < 20 low , 2025 normal , 25 overweight / obese ) . as done previously in the nett trial , dlco was treated as a binary variable , with a cut - off of < 22%.47 finally , multivariable analysis assessing the associations of age , sex , fev1 , dlco , ic , and bmi in conjunction with the ic / tlc ratio was performed . ic measurements were made during the enhanced spirometry section with deep inspiration occurring after a period of stable tidal breathing ; all tests were performed according to the american thoracic society ( ats ) criteria . single - breath dlco measurements were made according to ats criteria with a 10-second breath - hold ; correction for hemoglobin was not performed . forced expiratory spirometry was obtained pre- and post - spirometry ; plethysmography was obtained post - bronchodilator . numerical variables were summarized by mean and standard deviation or median and interquartile range ( iqr ) , as appropriate , depending on the normality of the distribution . group differences on numerical variables were assessed by student s t - tests ( normality was satisfied ) or the wilcoxon rank - sum test ( normality was violated ) . categorical variables were summarized by frequency and percentage and compared across groups by the chi - square test or fisher s exact test , as appropriate . factors associated with the risk of death were assessed by multivariable cox proportional hazards models . the proportional hazards assumption was assessed by the supremum test and by analysis of schoenfeld residuals . statistical calculations were made using sas software ( v9.1.3 ; sas institute inc . , cary , nc , usa ) . our database consisted of 39,050 pf tests ; 14,322 were excluded because they had no dlco recorded . the remaining 24,728 pfs that were excluded , either did not meet criteria for obstruction or were repeat pf tests . nine - hundred and eighty - four patient pfs meeting criteria were analyzed ( figure 1 ) . alive patients were younger , had a higher bmi , a higher fev1/fvc ratio , and higher predicted fev1 with a larger percentage being defined as having mild copd . in regards to lung volumes , alive patients had a slightly lower tlc , higher dlco , higher ic , and had better ic / tlc ratios than patients in the the potential predictors of all - cause mortality are shown in tables 2 and 3 . univariate analysis revealed that ic / tlc , % dlco , sex , age , bmi , ic , and fev1 were all significantly associated with survival ( table 2 ; figures 2 , 3 , and 4 ) . using an ic / tlc 25% compared to ic / tlc > 25% , there was a significant decrease in survival ( hr : 2.39 , 95% ci : 2.032.82 , p<0.0001 ) . the median survival was 4.3 years for ic / tlc 25% ( 95% ci : 3.84.9 years ) versus 11.9 years for ic / tlc > 25% ( 95% ci : 10.313.2 years ) . five - year survival for ic / tlc 25% versus ic / tlc > 25% was 43.9% ( 95% ci : 38.7%49.0% ) versus 73.4% ( 95% ci : 69.6%76.9% ) , respectively . additionally , a dlco < 22% versus a dlco 22% was associated with an increased risk of death ( hr : 2.08 , 95% ci : 1.682.57 , p<0.0001 ) . the median survival for a dlco < 22% was 3.77 years ( 95% ci : 2.944.60 years ) . females had reduced risk of death ( hr : 0.78 , 95% ci : 0.660.92 , p=0.003 ) . median survival for females was 8.7 years ( 95% ci : 7.710.1 years ) versus 7.0 years for males ( 95% ci : 5.78.2 years ) . a 5-year increase in age revealed a 23% increased risk of death ( hr : 1.23 , 95% ci : 1.181.28 , p<0.0001 ) . compared to a normal bmi ( 20 to < 25 , the reference level ) , patients with a bmi < 20 were at greater risk of death ( hr : 1.22 , 95% ci : 0.991.51 , p=0.068 ) . however , a bmi 25 appeared to be protective ( hr : 0.81 , 95% ci : 0.670.97 , p=0.022 ) . an ic 80% was associated with a reduced risk of death ( hr : 0.48 , 95% ci : 0.410.57 , p<0.0001 ) . lastly , fev1 was evaluated using moderate copd disease , as defined by gold criteria , as the reference group : patients with mild copd were less likely to die ( hr : 0.48 , 95% ci : 0.350.65 , p<0.001 ) ; however , both severe ( hr : 1.38 , 95% ci : 1.111.70 , p=0.003 ) and very severe copd ( hr : 1.81 , 95% ci : 1.462.23 , p<0.0001 ) patients were at increased risk of death . in addition , a multivariable analysis was preformed to assess the associations of age , sex , fev1 , % dlco , ic , and bmi in conjunction with the ic / tlc ratio . analysis revealed that age ( 5-year increase in age ) , sex , ic / tlc 25% , fev1 , bmi < 20 , and dlco < 22% remained statistically significant factors associated with the risk of death ( table 3 ) . patients with a dlco < 22% had an increased risk of death when compared to patients with a dlco 22% ( hr : 1.28 , 95% ci : 1.011.61 , p=0.043 ) ( figure 5 ) . compared to a normal bmi ( 20 to < 25 , the reference level ) , patients with a bmi < 20 were at greater risk of death ( hr : 1.22 , 95% ci : 0.971.53 , p=0.089 ) . in contrast , a bmi 25 appeared to be protective ( hr : 0.81 , 95% ci : 0.670.97 , p=0.022 ) ( figure 6 ) . lastly , fev1 was evaluated using moderate copd disease , as defined by gold criteria , as the reference group . patients with mild copd were less likely to die ( hr : 0.66 , 95% ci : 0.480.90 , p=0.009 ) . additionally , neither severe ( hr : 1.01 , 95% ci : 0.801.27 , p=0.95 ) nor very severe copd ( hr : 1.06 , 95% ci : 0.791.41 , p=0.71 ) patients were at increased risk of death , compared to the moderate group in the multivariate analysis . in summary , increasing age , ic / tlc 25% , dlco < 22% , and a bmi < 20 were associated with increased risk of death . lastly , we completed a univariate analysis of the ic / tlc ratio as a continuous predictor of the risk of death . over the entire range of ic / tlc ( 8%63% ) , a 10% decrease in ic / tlc was associated with a 66% increase in the risk of death ( hr : 1.66 , 95% ci : 1.521.81 , p<0.0001 ) . for clinical applicability , we categorized the ratio into four levels : ic / tlc > 45% ( the reference level ) , > 35% to 45% , > 25% to 35% , and 25% ( table 4 ; figure 7 ) . compared to patients with ic / tlc > 45% , patients with ic / tlc > 35% to 45% were at 76% increased risk of death ( hr : 1.76 , 95% ci : 1.072.89 ) ; patients with ic / tlc > 25% to 35% were at 182% increased risk of death ( hr : 2.82 , 95% ci : 1.764.53 ) ; and patients with ic / tlc 25% were at 423% increased risk of death ( hr : 5.23 , 95% ci : 3.288.35 ) . median survivals ( 95% ci ) were 4.3 ( 3.84.9 ) years for patients with ic / tlc 25% , 8.9 ( 7.710.5 ) years for patients with ic / tlc > 25% to 35% , and 14.1 ( 11.918.7 ) years for patients with ic / tlc > 35% to 45% . median survival was not yet reached in patients with ic / tlc > 45% ( 30-year survival estimate 52.3% ) . using an ic / tlc ratio of 25% , a representation of static lung hyperinflation , we were able to demonstrate that the ic / tlc ratio correlated with risk of death in patients with an emphysematous phenotype of copd . patients with an ic / tlc ratio 25% had a median survival of 4.3 years versus 11.9 years for those patients with an ic / tlc 25% . the use of the ic / tlc ratio , as a single predictor variable , in patients with copd , will allow clinicians to better evaluate and risk - stratify patients with an emphysematous phenotype of copd . in the 35 years since fletcher and peto described the natural history of copd , our understanding about the disease process has been an ongoing development.27 although initial studies supported fev1 as the best predictor of copd mortality,47 more recent literature has revealed that a variety of factors are more accurate predictors of mortality than fev1.7,1216,19,24,3439 interest has been shown in the role of the vitamin d pathway in copd , with vitamin d deficiency correlating with the risk of copd.26 in addition to ic / tlc and fev1 , we also examined the relationship of ic , age , bmi , dlco , and sex ( tables 1 and 3 ) and their associations with the risk of death . specifically , our multivariable analysis demonstrated that ic alone was not a reliable predictor of mortality , contrary to what has been previously reported in a milder copd population.24 we were able to demonstrate that age and bmi were associated with risk of death but did not demonstrate as clear an association as the ic / tlc . in regards to sex , kaplan meier analysis revealed that females had a survival advantage when compared directly to males with copd . ringbaek et al previously reported that when compared to standardized mortality rates expected in the general population , it appeared that females with copd actually have more years of life lost than their male counterparts.21 furthermore , when examining the dlco , we found a significant association with risk of death . to our knowledge , it is the first study to evaluate mortality over 34 years of reported data in an emphysematous phenotype of copd . additionally , our cohort consisted of 44.3% ( 436 ) females , and to date , is one of the largest cohorts of females used to evaluate copd mortality . we used an easily identifiable ic / tlc cut - off of 25% , which has previously been validated.7 the study does have limitations . it is a pf test - based study , assumptions about the patients clinical phenotype were made on the basis of pf data , and no smoking history or radiological data were available . we did not evaluate or compare the bode index or 6mwt . on the other hand , we did evaluate other well - defined variables including age , bmi , and fev1 in the analysis . we did not have pao2 values , therefore could not evaluate / correlate the degree of hypoxemia and its role in survival . the study inclusion criteria required a dlco for the patient to be included in the analysis . in doing so , we eliminated patients who may have obstructive disease secondary to asthma , but undoubtedly removed many patients with copd . we did not evaluate specific cause of death as previous studies have done , which prevented us from excluding patients that died from nonrespiratory events . our study demonstrates that the ic / tlc ratio 25% is strongly related to risk of death in an emphysematous phenotype of copd patients . when compared to fev1 and other previously accepted variables , ic / tlc was a better predictor of survival in both univariate and multivariate analysis . specifically , we found fev1 to be weakly associated with survival . when using patients with moderate severity as the reference group , those patients with mild disease were noted to have improved survival . patients with severe and very severe disease did not have a statistically significant difference in mortality when compared to those individuals with moderately severe disease . we believe that the reduced ic / tlc ratio , reflective of static lung hyperinflation , plays an important role in patients with an emphysematous phenotype of copd . dynamic lung hyperinflation is associated with increasing end - expiratory lung volumes , which is associated with airflow limitation and loss of elastic recoil . in copd , emphysematous changes in the lung are secondary to destruction of the elastic tissue in the lung parenchyma . as the lung parenchyma loses it elasticity , lung recoil is reduced , resulting in a compensatory increase in functional reserve capacity ( frc ) ; as the frc increases , the ic is reduced.49 therefore , in patients with copd , the relationship between ic and tlc gradually declines as static lung hyperinflation increases . in addition to risk of death , static lung hyperinflation has been reported to correlate with exercise capacity and cardiac performance in patients with copd , thus adding to the clinical use of the ic / tlc ratio . previous studies of copd patients often refer to the fev1 and its rate of decline to define treatment success or failure . current treatment guidelines are based on the gold - defined fev1 , an endpoint that we found to have little correlation with survival . we believe that the ic / tlc ratio may be a more relevant variable for such analysis , possible arguing for further studies . in conclusion , a significant number of copd patients have pf tests that include measurement of lung volumes . the ic / tlc ratio , like the bode index , has demonstrated a correlation with copd survival , is easy to obtain , and should be considered in the assessment of patients with an emphysematous phenotype of copd .
backgroundforced expiratory volume in 1 second ( fev1 ) grades severity of copd and predicts survival . 
 we hypothesize that the inspiratory capacity / total lung capacity ( ic / tlc ) ratio , a sensitive measure of static lung hyperinflation , may have a significant association with survival in an emphysematous phenotype of copd.objectivesto access the association between ic / tlc and survival in an emphysematous phenotype of copd.methodswe performed a retrospective analysis of a large pulmonary function ( pf ) database with 39,050 entries , from april 1978 to october 2009 . 
 emphysematous copd was defined as reduced fev1/forced vital capacity ( fvc ) , increased tlc , and reduced diffusing capacity of the lungs for carbon monoxide ( dlco ; beyond 95% confidence intervals [ cis ] ) . 
 we evaluated the association between survival in emphysematous copd patients and the ic / tlc ratio evaluated both as dichotomous ( 25% vs > 25% ) and continuous predictors . 
 five hundred and ninety - six patients had reported death dates.resultsunivariate analysis revealed that ic / tlc 25% was a significant predictor of death ( hazard ratio [ hr ] : 2.39 , p<0.0001 ) . 
 median survivals were respectively 4.3 ( 95% ci : 3.84.9 ) and 11.9 years ( 95% ci : 10.313.2 ) . 
 multivariable analysis revealed age ( hr : 1.19 , 95% ci : 1.141.24 ) , female sex ( hr : 0.69 , 95% ci : 0.600.83 ) , and ic / tlc 25% ( hr : 1.69 , 95% ci : 1.342.13 ) were related to the risk of death . 
 univariate analysis showed that continuous ic / tlc was associated with death , with an hr of 1.66 ( 95% ci : 1.521.81 ) for a 10% decrease in ic / tlc.conclusionadjusting for age and sex , ic / tlc 25% is related to increased risk of death , and ic / tlc as a continuum , is a significant predictor of mortality in emphysematous copd patients .