Does A Normal FEV1/FVC Ratio In Patients With Normal FEV1 And FVC Rule Out Obstructive Lung Disease?
Spyridon Fortis1,2*, David R Jacobs3, Edward O Corazalla4 and Hyun J Kim1,4
1Pulmonary and Critical Care Division, Department of Medicine, University of Minnesota, USA
2Pulmonary and Critical Care Division, Department of Medicine, University of Iowa, USA
3Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, USA
4Pulmonary Function Test Laboratory, University of Minnesota Medical Center, USA
*Correspondance to: email@example.com
Copyright: © 2017 The Authors. Published by Scientific Open Access Journals LLC.
Citation: Fortis S, Jacobs DR, Corazalla EO, et al. Does A Normal FEV1/FVC Ratio In Patients With Normal FEV1 And FVC Rule Out Obstructive Lung Disease? J Pulmonol Respir Ther 2017; 1:001.
Received: 17 October 2016; Accepted: 12 December 2016; Published: 02 January 2017
In individuals with both normal FEV1 and FVC, a normal ratio can discourage a health care provider from pursuing further diagnostic work up and therefore they are at risk for misdiagnosis. Our objective was to examine whether a normal FEV1/FVC in individuals with both normal FEV1 and FVC is sufficient to rule out obstructive lung disease. We compared retrospectively the sensitivity and specificity of FEV1/FVC below the lower limit of normal, FEV1/FVC below 0.7, and air trapping and/or hyperinflation by plethysmography to diagnose radiographic obstructive lung disease. We included 455 patients, 80 (17.6%) of whom had radiographic findings of obstructive lung disease. The sensitivities of all 3 diagnostic criteria to diagnose radiographic obstructive lung disease were below 19%. Positive (PPVs) were 12.1-16.3% for each criterion, while negative predictive values (NPVs) were 80.4-82.3%. In patients with both normal FEV1 and FVC, a normal FEV1/FVC is associated with approximately 20% probability of radiographic findings of obstructive lung disease.
Keywords: Chronic obstructive pulmonary disease; Emphysema; Radiographic tomography; Respiratory function tests; Spirometry
A plethora of studies have investigated whether an FEV1/FVC ratio below the lower limit of normal (LLN)  or a fixed ratio below 0.7  should be used to diagnose obstructive lung disease. An abnormal FEV1 or FVC in combination with respiratory symptoms even with a normal FEV1/FVC ratio can trigger further investigations, e.g. lung volumes, diffusion capacity measurements or imaging of the chest [3,4]. However, in an individual with both normal FEV1 and FVC, a normal ratio can discourage a health care provider from pursuing further testing to diagnose a respiratory cause of the patient’s symptom and therefore, they are at risk for misdiagnosis. Our objective was to examine whether a normal FEV1/FVC ratio in individuals with both normal FEV1 and FVC is sufficient to rule out obstructive lung disease. We reviewed pulmonary function tests of patients in our database that had both normal FEV1 and FVC. In the absence of a true gold standard test for obstructive lung disease, we used radiographic chest computed tomography (CT) findings like air trapping (AT) and emphysema to define obstructive lung disease. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FEV1/FVC ratio and AT and/or hyperinflation based on plethysmography for chest radiographic findings of obstructive lung disease in chest CTs.
The study protocol was reviewed and approved on September 1 2014 (exempt status, study number: #1408E53103), by the University of Minnesota Institutional Review Board, in accordance with the Code of Federal Regulations, 45 CFR 46.101(b). To construct our analysis dataset, we retrieved data from our previous adult pulmonary function test database with 1805 patients . All pulmonary function tests were performed according to American Thoracic Society- European Respiratory Society (ATS-ERS) guidelines and met the ATS-ERS standards for acceptability and repeatability [2-4]. Pulmonary function tests were performed by using Medical Graphics Diagnostics Corporation equipment and BreezeSuite™ version 7.1 software. We extracted the following data from each pulmonary function test record: patient age, race, height, sex, weight, FEV1 (L), FEV1 % predicted, FVC (L), FVC % predicted, FEV1/FVC, residual volume (RV) (L), RV % predicted, total lung capacity (TLC) (L), TLC % predicted, and RV/TLC % predicted.
After excluding 15 lung transplant patients, 764 patients had pulmonary function tests with both normal FEV1 and FVC according to the Hankinson predicted values . Among these, we included only patients in whom chest CT was clinically indicated and performed. One of the authors reviewed the electronic medical record (EMR) at least 6 months after the pulmonary function tests for clinical diagnosis by health care provider, radiographic findings of obstructive lung disease in chest CT reports, and smoking history.
First, we reviewed the past medical history and problem list, which are distinct data in the electronic medical record. Second, we reviewed health-care provider notes to confirm a clinical diagnosis starting from the most recent encounter. We defined as obstructive lung disease the following respiratory clinical diagnoses: asthma, bronchiolitis, bronchitis, COPD and emphysema. We defined as dyspnea or cough when the patients carried only those diagnoses in their chart. We defined as other respiratory diagnosis the following respiratory clinical diagnoses: alveolar proteinosis, bronchiectasis, follicular bronchiolitis, desquamative interstitial pneumonia, lung cancer, myopathy, primary pulmonary hypertension, pulmonary embolism, respiratory bronchiolitis and sarcoidosis. If patients carried both an obstructive lung disease and ILD diagnosis, we recorded it as other respiratory diagnosis. If patients carried both a cough or dyspnea diagnosis with an obstructive lung disease diagnoses, ILD or other respiratory diagnosis, we discarded cough or dyspnea diagnosis.
Radiographic findings of obstructive lung disease were defined as the presence of “air trapping” and “emphysema” in chest CT reports. We did not examine what criteria were used by the health care providers and radiologists for those diagnoses.
We compared the sensitivity and specificity of three diagnostic criteria to detect radiographic findings of obstructive lung disease, as defined above: 1) FEV1/FVC<LLN , 2) FEV1/FVC<0.7 (GOLD) , and 3) AT and/or hyperinflation based on the plethysmographic lung volume measurement . AT and/or hyperinflation based on plethysmography was defined as RV, RV/TLC or TLC  above the upper limit of normal (ULN) . We calculated PPV and NPV for all 3 diagnostic criteria.
We compared sensitivity and specificity for radiographic findings of obstructive lung disease of the above criteria in the total sample and after stratification by age, BMI, sex and smoking status. To compare sensitivities and specificities among the different diagnostic criteria, we used the McNemar test . All analyses were carried out using Epi Info 7 statistical software and online GraphPad software calculators.
We included 455 patients, 59 (13%) of whom had radiographic AT, 33 (7.3%) had emphysema and 80 (17.6%) had AT and/or emphysema. Table 1 presents the characteristics of our sample. The sensitivity to detect radiographic findings of obstructive lung disease did not vary among the different diagnostic criteria (Table 2). The sensitivity of the LLN criterion was 8.8%, of the GOLD criterion was 11.3% (p=0.68 vs LLN), and of plethysmography was 18.5% (p=0.10 vs LLN). The GOLD criterion sensitivity was superior to sensitivity of plethysmography (p<0.0001). The LLN criterion showed significantly higher specificity (90.4%) than the GOLD criterion (85.9%; p=0.004) or plethysmography (70.9%; p<0.0001). PPVs were low (12.1-16.3%) for each of the criteria, while NPVs were between 80.4-82.3% (Table 2). Sensitivities and specificities were not improved when looking at radiographic AT or emphysema separately (data not shown).
The sensitivity and specificity of the 3 diagnostic criteria stratified by age, BMI and smoking status are presented in Figure 1. The sensitivity was similar across strata among all 3 diagnostic criteria, and specificity followed the same pattern as in the total sample (the LLN criterion > the GOLD criterion > plethysmography) when stratified by sex (data not shown).
In this clinical sample, the FEV1/FVC ratio demonstrates very poor sensitivity to detect radiographic findings of obstructive lung disease seen on chest CT scans in patients with normal FEV1 and FVC regardless of whether the LLN or a fixed 0.7 ratio is used as a threshold. The specificity of the LLN criterion is significantly higher than the GOLD criterion. AT and/or hyperinflation based on plethysmography shows both poor sensitivity and specificity. PPVs were low (12.1-16.3%) for each of the criteria, while NPVs were between 80.4-82.3%.
Some reports have shown that FEV1/FVC< LLN is associated with a greater risk of death and respiratory symptoms compared to FEV1/FVC< 0.7 , while other studies indicate that patients with FEV1/FVC ratio< 0.7 are more likely to die and be hospitalized . However, these studies were not restricted to patients with normal FEV1 and FVC, in whom the utility of these criteria could be different. A recent study showed that the LLN criterion underdiagnoses patients with radiographic evidence of COPD compared to using the fixed ratio . In the present study that includes only individuals with normal FEV1 and FVC, both the LLN and the GOLD criterion demonstrated poor sensitivity for detecting obstructive lung disease radiographic findings.
Interestingly, lung volumes measurements by plethysmography showed poor sensitivity and specificity for AT on chest CT scans although they are intended to measure the same pathophysiologic phenomenon. Plethysmography often overestimates lung volumes compared to chest CT . This discordance could be due to the fact that plethysmography is performed in sitting position while CT is perform in the supine position and due to the fact that predicted values for TLC, RV and RV/TLC are derived from obstructive lung disease studies in samples which are not representative of our subjects .
The poor performance of the above criteria to detect radiographic findings of obstructive lung disease in people with normal FEV1 and FVC could relate to the heterogeneity of obstructive lung diseases like COPD. Up to 42% of patients with FEV1/FVC>0.7 have emphysema on chest CT . Nevertheless, radiographic emphysema has important prognostic value as it was associated with a greater risk for lung function decline even in patients with normal FEV1/FVC ratio . Similarly, other obstructive lung diseases like asthma may have different phenotypes .
In our sample of people with normal FEV1 and FVC and a low prevalence of radiographic obstructive lung disease patients, patients with normal FEV1/FVC ratio according to either LLN or GOLD criteria still have about 20% probability of having radiographic findings of obstructive lung disease (NPV is about 80%). Many who fulfill the LLN or GOLD criteria do not have radiographic findings of obstructive lung disease (PPV is about 15%). This probably reflects the fact that only a portion of patients with obstructive ventilatory defect on spirometry will have radiographic findings of obstructive lung disease .
Patients with COPD or asthma and normal FEV1 and FVC have mild symptoms, and they use health care less compared to patients with moderate or severe disease . Nevertheless, establishing the diagnosis even in the early stages may encourage smokers to quit smoking  leading to improved outcomes . Patients with radiographic emphysema are also at risk for future decline in lung function . Therefore, further investigation of respiratory symptoms with a chest CT  or diffusion capacity  should be considered in patients with high risk factors for obstructive lung disease like smoking.
Limitations of our study are the retrospective and cross-sectional design. We did not examine how many chest CTs included expiratory images. Also, the interpretation of chest CT scans was not standardized, and healthy elderly subjects may have been “overdiagnosed” by the radiologist. However, stratification by age showed no difference in sensitivity and specificity. Moreover, visual assessment by radiologists has been shown to provide additional information to the radiographic findings of obstructive lung disease detected by software . Since, we aimed to investigate whether a normal FEV1/FVC ratio in individuals with respiratory symptoms and both normal FEV1 and FVC is sufficient to rule out obstructive lung disease, we grouped AT and emphysema together although we recognize that AT can be present in both asthma and COPD while emphysema is a feature of COPD only. However, when we evaluated radiographic AT and emphysema separately, we did not see any improvement in sensitivity and specificity. Lastly, the subject sample was racially homogenous (almost all Caucasian).
Despite the fact that we did not have expiratory cuts for all the chest CTs, which would have likely reduced further the sensitivity of FEV1/FVC as we would have detected more radiographic AT, our findings are clinically relevant and suggest that the value of FEV1/FVC to detect (radiographic) obstructive lung disease is poor when health care providers see patients with both normal FEV1 and FVC in the clinic.
In patients with normal FEV1 and FVC, the sensitivity of FEV1/FVC ratio to detect radiographic findings of obstructive lung disease is poor regardless of whether the threshold is the LLN or the fixed 0.7 ratio. A patient with normal a FEV1/FVC ratio has approximately 20% probability of having radiographic findings of obstructive lung disease. Further investigation of respiratory symptoms with a chest CT or diffusion capacity should be considered in patients with “normal” FEV1, FVC, and ratio if there is a high index of suspicion to rule out obstructive lung disease.
- Vaz Fragoso CA, Concato J, Mcavay G, Van Ness PH, Rochester CL, Yaggi HK, et al.. The ratio of FEV1 to FVC as a basis for establishing chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010; 181:446-451.
- Mannino DM, Sonia Buist A, Vollmer WM. Chronic obstructive pulmonary disease in the older adult: what defines abnormal lung function? Thorax. 2007; 62:237-241.
- Barjaktarevic I, Springmeyer S, Gonzalez X, Sirokman W, Coxson HO, Cooper CB. Diffusing capacity for carbon monoxide correlates best with tissue volume from quantitative CT scanning analysis. Chest. 2015; 147:1485-1493.
- Coxson HO, Leipsic J, Parraga G, Sin DD. Using pulmonary imaging to move chronic obstructive pulmonary disease beyond FEV1. Am J Respir Crit Care Med. 2014; 190:135-144.
- Fortis S, Corazalla EO, Wang Q, Kim HJ. The difference between slow and forced vital capacity increases with increasing body mass index: a paradoxical difference in low and normal body mass indices. Respir Care. 2015; 60:113-118.
- Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999; 159:179-187.
- Pauwels R. Global initiative for chronic obstructive lung diseases (GOLD): time to act. Eur Respir J. 2001; 18:901-902.
- Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005; 26:948-968.
- Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC.. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993; 16:5-40.
- Trajman A, Luiz RR. McNemar chi2 test revisited: comparing sensitivity and specificity of diagnostic examinations. Scand J Clin Lab Invest. 2008; 68:77-80.
- Bhatt SP, Washko GR, Dransfield MT, Sieren JC, Newell JD Jr, Hoffman EA. Comparison of spirometric thresholds in diagnosing smoking-related airflow obstruction: authors' response. Thorax 2014; 69:1147-1148.
- Garfield JL, Marchetti N, Gaughan JP, Steiner RM, Criner GJ.. Total lung capacity by plethysmography and high-resolution computed tomography in COPD. Int J Chron Obstruct Pulmon Dis. 2012; 7:119-126.
- Regan EA, Lynch DA, Curran-Everett D, Curtis JL, Austin JH, Grenier PA, et al. Clinical and Radiologic Disease in Smokers With Normal Spirometry. JAMA Intern Med. 2015; 175:1539-1549.
- Mohamed Hoesein FA, de Hoop B, Zanen P, Gietema H, Kruitwagen CL, van Ginneken B, et al. CT-quantified emphysema in male heavy smokers: association with lung function decline. Thorax. 2011; 66:782-787.
- Busacker A, Newell JD Jr, Keefe T, Hoffman EA, Granroth JC, Castro M. A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis. Chest. 2009; 135:48-56.
- Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med. 2006; 119:21-31.
- de Torres JP, Bastarrika G, Zagaceta J, Sáiz-Mendiguren R, Alcaide AB, Seijo LM, et al. Emphysema presence, severity, and distribution has little impact on the clinical presentation of a cohort of patients with mild to moderate COPD. Chest. 2011; 139:36-42.
- Parkes G, Greenhalgh T, Griffin M, Dent R. Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial. BMJ. 2008; 336:598-600.
- Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE, et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005; 142:233-239.
- Kim SS, Seo JB, Lee HY, Nevrekar DV, Forssen AV, Crapo JD, et al. Chronic obstructive pulmonary disease: lobe-based visual assessment of volumetric CT by Using standard images--comparison with quantitative CT and pulmonary function test in the COPDGene study. Radiology. 2013; 266:626-635.