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Accuracy of diagnosis of COPD and factors associated with misdiagnosis in primary care setting. E-DIAL (Early DIAgnosis of obstructive lung disease) study group

  • Author Footnotes
    1 These authors contributed equally to this work as first authors.
    Stefano Nardini
    Footnotes
    1 These authors contributed equally to this work as first authors.
    Affiliations
    Division of Respiratory Medicine, Vittorio Veneto Hospital, Vittorio Veneto, Italy
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  • Author Footnotes
    1 These authors contributed equally to this work as first authors.
    Isabella Annesi-Maesano
    Correspondence
    Corresponding author. Epidemiology of Allergic and Respiratory Diseases Department (EPAR), i-PLESP, Saint-Antoine Medical School, 27 rue Chaligny, CEDEX 12, 75571, Paris, France.
    Footnotes
    1 These authors contributed equally to this work as first authors.
    Affiliations
    Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France
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  • Marzia Simoni
    Affiliations
    Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France
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  • Adriana del Ponte
    Affiliations
    Division of Respiratory Medicine, Chieti Hospital, Chieti, Italy
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  • Claudio Maria Sanguinetti
    Affiliations
    Division of Respiratory Medicine, Santo Spirito Hospital, Rome, Italy
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  • Fernando De Benedetto
    Affiliations
    Division of Respiratory Medicine, Chieti Hospital, Chieti, Italy
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  • Author Footnotes
    1 These authors contributed equally to this work as first authors.
Open ArchivePublished:August 17, 2018DOI:https://doi.org/10.1016/j.rmed.2018.08.006

      Highlights

      • COPD is a silent killer that is often diagnosed too late and constitutes a major health concern nowadays.
      • Our results confirm that COPD misdiagnosis is common in primary care and in particular that under-diagnosis is a major problem. Lack of precision in COPD diagnosis resulted in 13% of over-diagnosis and 59% of under-diagnosis.
      • Having performed a previous spirometry and self-reported symptoms of chronic cough, phlegm and dyspnea were the only factors that significantly decreased the risk for undiagnosed COPD (by about 4 folds each).
      • Our findings have to be applied in clinical settings.

      Abstract

      Background

      Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide and results in both substantial and increasing socioeconomic burden. Guidelines on COPD encourage primary care physicians to detect the disease at an early stage. Our main aim was to evaluate the accuracy of the diagnosis of COPD at the primary health care.

      Methods

      6466 patients were randomly selected in 22 Italian primary care practices (46% males, mean age 56 ± 16 years) and were asked about respiratory symptoms and risk for any chronic respiratory disease including COPD. After a prior evaluation, 701 patients (51% males, mean age 59 ± 15 years) were sent by General Practitioners (GPs) to Pulmonary Units (PU) for confirming the diagnosis. The agreement in diagnosing COPD between GPs and pulmonary diseases specialists was assessed by using Cohen's kappa (k) statistic.

      Results

      Lack of precision in COPD diagnosis resulted in 13% of over-diagnosis and 59% of under-diagnosis. GPs were quite good in correctly excluding the patients who did not have COPD (specificity = 87%), but less good in diagnosing the patients with COPD (sensitivity = 41%). The risk of under-diagnosis was higher in people with age >62 years and in current/ex-smokers, when compared to no COPD, whereas it was higher in subject <62 years old and in those with no previous spirometry when compared to correctly diagnosed COPD.

      Conclusion

      Our results confirm that COPD misdiagnosis is common in primary care and that under-diagnosis is a major problem. It is necessary to enhance COPD diagnosis and to reduce misdiagnosis in primary care settings.

      Keywords

      1. Introduction

      Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases [
      ]. Besides tobacco smoking that is directly and positively related to COPD, other major risk factors independently associated with COPD are cumulative environmental and occupational exposures, poor socioeconomic status, and older age.
      Worldwide, COPD is a leading cause of morbidity and mortality, and results in an economic and social burden that is both substantial and increasing. Population surveys have identified large differences in the distribution of the prevalence of COPD that globally has been estimated to range from 4% to 20% in adults over 40 years of age, which correspond to an underestimation of the COPD that is rarely diagnosed in its mild forms. In addition, it is estimated that about 3 million deaths were caused by COPD in 2015 (5% of all deaths) in the world. Projection estimates show that COPD becomes in 2030 the third leading cause of death worldwide.
      However, the real burden of COPD is unknown. The mortality due to COPD is underreported in the death certificates [
      • Faustini A.
      • Marino C.
      • D'Ovidio M.
      • Perucci C.A.
      The concurrent COPD mortality doubles the mortality estimate from COPD as underlying cause in Lazio, Italy.
      ]. Furthermore, figures are incomplete for COPD morbidity. Underdiagnosis of COPD remains constantly high in Europe and elsewhere, with figures ranging from 70% to 90% and even higher. It was calculated that with an underdiagnosis rate of 70%, about 28 million Europeans are not yet diagnosed, therefore remaining untreated [
      ]. Yet, the epidemic of COPD can be combatted only through prevention (primary and secondary) and an integrated treatment of the disease after a correct diagnosis. Accurate diagnosis of COPD is important also to avoid unnecessary costs and potential side-effects in those unlikely to benefit from therapy [
      ].
      People with known risk factors for COPD are important targets for screening and early intervention [
      • Hill K.
      • Goldstein R.S.
      • Guyatt G.H.
      • Blouin M.
      • Tan W.C.
      • Davis L.L.
      • Heels-Ansdell D.M.
      • Erak M.
      • Bragaglia P.J.
      • Tamari I.E.
      • Hodder R.
      • Stanbrook M.B.
      Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care.
      ]. Early diagnosis, that should always be understood as a clinical, not just functional, diagnosis, is considered important because it enables one to act immediately on the causes of disease (first of all, cigarette smoking) to impede or delay the effects of the progression of respiratory disease towards more severe and invalidating symptom levels [
      • Nardini S.
      • Annesi-Maesano I.
      • Del Donno M.
      • Delucchi M.
      • Bettoncelli G.
      • Lamberti V.
      • Patera C.
      • Polverino M.
      • Russo A.
      • Santoriello C.
      • Soverina P.
      The AIMAR recommendations for early diagnosis of chronic obstructive respiratory disease based on the WHO/GARD model*.
      ]. Problems in guideline implementation include difficulties in diagnosis, using spirometry and the disputed role of reversibility testing. In Italy, COPD care is generally still inadequate. Existing guidelines, institutional and non-institutional, are inadequately implemented: the international guidelines are not always adaptable to the local context [
      • Nardini S.
      • Annesi-Maesano I.
      • Del Donno M.
      • Delucchi M.
      • Bettoncelli G.
      • Lamberti V.
      • Patera C.
      • Polverino M.
      • Russo A.
      • Santoriello C.
      • Soverina P.
      The AIMAR recommendations for early diagnosis of chronic obstructive respiratory disease based on the WHO/GARD model*.
      ].
      Guidelines on COPD diagnosis and management encourage to detect the disease at an early stage also because it has been pointed out that most rapid decline in lung function may occur much earlier than previously thought [
      • Tantucci C.
      • Modina D.
      Lung function decline in COPD.
      ]. General Practitioner (GP) appears to be strategic in early diagnosis [
      • Jones R.C.
      • Price D.
      • Ryan D.
      • Sims E.J.
      • von Ziegenweidt J.
      • Mascarenhas L.
      • Burden A.
      • Halpin D.M.
      • Winter R.
      • Hill S.
      • Kearney M.
      • Holton K.
      • Moger A.
      • Freeman D.
      • Chisholm A.
      • Bateman E.D.
      Respiratory Effectiveness G. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort.
      ].
      While there is general agreement that GPs can play a pivotal role in COPD early diagnosis [
      • Ulrik C.S.
      • Lokke A.
      • Dahl R.
      • Dollerup J.
      • Hansen G.
      • Cording P.H.
      • Andersen K.K.
      group TOPs
      Early detection of COPD in general practice.
      ], evidence coming from other studies has shown failures in diagnosis [
      • Jones R.C.
      • Price D.
      • Ryan D.
      • Sims E.J.
      • von Ziegenweidt J.
      • Mascarenhas L.
      • Burden A.
      • Halpin D.M.
      • Winter R.
      • Hill S.
      • Kearney M.
      • Holton K.
      • Moger A.
      • Freeman D.
      • Chisholm A.
      • Bateman E.D.
      Respiratory Effectiveness G. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort.
      ] as well as barriers to diagnosing COPD in primary care due to insufficient expertise [
      • Haroon S.
      • Jordan R.E.
      • Fitzmaurice D.A.
      • Adab P.
      Case finding for COPD in primary care: a qualitative study of the views of health professionals.
      ]. The purpose of the present study was to evaluate the ability of GPs to screen people with COPD in the multicenter project called E-DIAL (Early DIAgnosis of obstructive Lung disease) conducted in Italy aiming at revealing the extent of misclassification, both underdiagnosis and overdiagnosis, of COPD and to evidence the possible causes of it.

      2. Methods

      The protocol of the E-DIAL study established among experts during ad hoc meetings was applied.

      2.1 Recruitment

      Six hundred height six GPs from 23 Italian primary care practices randomly recruited 7028 patients, and invited them to complete a screening questionnaire, including information on gender, age, smoking habit, education, environmental/occupational exposure, and respiratory symptoms/diagnoses. In practice, each GP during his/her consultations had to recruit the first 10 patients of a day drawn at random by the organizers. This could happen in the morning as well as in the afternoon and sometimes at the end of the day according to the consultation schedule. The survey was stopped when 10 patients had accepted to participate, but 84 GPs recruited 12 patients. The patients who completed the screening standardized questionnaire were 6466 (participation rate 92%, 46% males, mean age 56 ± 16 years). Among them, 701 (51% males, mean age 59 ± 15 years) were sent to Pulmonary Units (PUs) by GPs for confirming a diagnosis of chronic respiratory disease, and particularly of COPD, based on the responses in the questionnaire, the anamnesis and the clinical visit. As requested by the Italian legislation, the patients were informed about the objectives of the survey and signed an informed consent.

      2.2 Definitions

      Respiratory health outcomes collected in the E-DIAL study with a standardized questionnaire resulting from the fusion of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (https://goldcopd.org/wp-content/uploads/2016/12/wms-GOLD-2017-Pocket-Guide.pdf) and the European Community Respiratory Health Survey (ECRHS) (http://www.ecrhs.org/quests.htm) questionnaires included:
      • 1.
        Usual cough/phlegm (question: “Have you cough (or phlegm) for most days a week for at least 3 months a year apart from common cold/flu?”);
      • 2.
        Current wheeze (“Have you had attacks of wheezing or whistling with shortness of breath in the last 12 months?”);
      • 3.
        Dyspnoea (“Have you shortness of breath when hurrying on level ground or walking up a slight hill, or shortness of breath sensation at rest?”);
      • 4.
        Emphysema (“Has a doctor ever told you that you have emphysema?”);
      • 5.
        Asthma (“Has a doctor ever told you that you have asthma?”, “At what age began asthma?” “You still have asthma?”);
      • 6.
        Rhinitis: (“Have you ever had hay fever or an allergic problem with a runny or blocked nose when you did not have a cold?”, “Have you ever had an allergic problem with reddish, itchy, watery eyes?”, “You still have rhinitis”?);
      • 7
        Allergy (“Have you any respiratory allergy?”).
      • 8
        Chronic respiratory disease (CRD) includes asthma, COPD, chronic bronchitis, pneumonia, and rhinitis.

      2.3 Spirometry

      At the PUs, 99% of the patients (n = 697) performed pre- and post-bronchodilator (400 μg of salbutamol) spirometry according to the American Thoracic Society criteria of acceptability and reproducibility. The diagnostic criteria for COPD adopted by pulmonologists were the post-bronchodilator FEV1/FVC fixed ratio of <0.70 (GOLD criterion) for 77% of cases, and pre-bronchodilator FEV1/FVC ratio of <0.70 less than the lower limit of normal values (LLN) (ATS/ERS criterion) [
      • Pellegrino R.
      • Viegi G.
      • Brusasco V.
      • Crapo R.O.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • van der Grinten C.P.
      • Gustafsson P.
      • Hankinson J.
      • Jensen R.
      • Johnson D.C.
      • MacIntyre N.
      • McKay R.
      • Miller M.R.
      • Navajas D.
      • Pedersen O.F.
      • Wanger J.
      Interpretative strategies for lung function tests.
      ] for 23% of cases. LLN is defined as that value which identifies the lower 5th centile of a healthy population of non-smokers [
      ]. The diagnoses made at PUs were considered as gold standard to evaluate the diagnostic accuracy of GPs.

      2.4 Statistical methods

      2.4.1 Accuracy of the diagnosis

      COPD diagnoses made by GPs were compared to COPD diagnoses made by the pulmonary diseases doctors (reference standard) through contingency tables. We initially conducted a classical diagnosis test evaluation by computing sensitivity, specificity, positive and negative likelihood ratios and positive and negative predictive values respectively. They were defined as follows:
      • -
        Sensitivity: probability that a GP-diagnosis will be positive when the disease is present according to the pulmonologist (true positive rate);
      • -
        Specificity: probability that a GP-diagnosis will be negative when the disease is not present (true negative rate);
      • -
        Positive likelihood ratio: ratio between the probability of a positive GP-diagnosis given the presence of the disease and the probability of a positive GP-diagnosis given the absence of the disease (i.e. True positive rate/False positive rate = Sensitivity/(1-Specificity); the positive likelihood ratios will be taken into account when they are in the range of 2 or more, and are useful from a clinical point of view when they are greater than 5;
      • -
        Negative likelihood ratio: ratio between the probability of a negative GP-diagnosis given the presence of the disease and the probability of a negative GP-diagnosis given the absence of the disease (i.e. False negative rate / True negative rate = (1-Sensitivity)/Specificity); for negative likelihood ratios, the values to be considered are those smaller than 0.1;
      • -
        Positive predictive value: probability that the disease is present when the diagnosis is positive;
      • -
        Negative predictive value: probability that the disease is not present when the diagnosis is negative.
      Successively, the agreement between GPs and pulmonologists was assessed by using Cohen's kappa (k) statistics [
      • Landis J.R.
      • Koch G.G.
      An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers.
      ] that determines the level of agreement between 2 authors who are assigning one of n categories to m subjects, taking into account the agreement occurring by chance. The k index ranges from 0 (absence of agreement) to 1 (perfect agreement). A value less than 0.20 indicates slight agreement, from 0.21 to 0.40 fair, from 0.41 to 0.60 moderate, from 0.61 to 0.80 good, and higher than 0.81 almost perfect agreement. The results were reported as k and 95% Confidence Interval (CI). Since it has been observed that k may tend to underestimate the agreement [
      • Strijbos J.M.R.
      • Prins F.
      • Jochems W.
      Content analysis: what are they talking about?.
      ], the absolute agreement (accordance to the reference standard regarding both the presence and the absence of the disease) was also considered.

      2.4.2 Factors related to accuracy of the diagnosis

      We run bivariate and multivariate logistic regression models to explore the association between the accuracy of COPD diagnosis by GPs (dependent variable) and the following independent variables: age, gender, smoking status (current/ex versus never), presence of obesity, diagnostic use of spirometry. Additional analyses included also the number of respiratory symptoms (chronic cough and/or chronic phlegm without dyspnea, or both chronic cough and chronic phlegm plus dyspnea). After having introduced four groups, the accuracy of the diagnosis was dichotomized in separate analyses as:
      • 1.
        Undiagnosed COPD versus no COPD,
      • 2
        Overdiagnosed COPD versus correctly diagnosed COPD,
      • 3
        Undiagnosed COPD versus correctly diagnosed COPD.
      Statistical analyses were performed with SPSS version 17 (SPSS Inc, Chicago, IL). Used routines were: frequency analysis, contingency tables, chi-square test, kappa statistic, non-parametric test U of Mann-Withney, logistic regression analysis. We considered p values of 0.05 or less as significant.

      3. Results

      The patients sent to the PUs, compared to those who were not, were significantly older, more frequently males, not working, current/ex-smokers, less educated, and showed higher frequency of a lifetime occupational exposure to dust (Table 1). More than half (53%) of the patients sent to the PUs reported past year wheezing, 26% usual phlegm, 35% usual cough, and 32% any dyspnea; the majority of the patients (66.5%) reported at least a lifetime diagnosis of respiratory disease, more frequently asthma (24%) and rhinitis (17%), and 10% reported a diagnosis of emphysema (Table 2). GPs set a diagnosis of CRD for 71.5% of the patients (n = 501); specifically, COPD was diagnosed in 18% of cases (n = 127) (Table 2). GPs declared they based the diagnosis of COPD on spirometric values in 55% of cases. The reasons for sending to the PUs other 200 patients with no specific diagnosis were the presence of respiratory symptoms suggesting a chronic respiratory disease, or high/very high risk for COPD based on the Italian risk cards [
      • Zuccaro P.P.S.
      • Mortali C.
      • Pacifici R.
      • Viegi G.
      • Baldacci S.
      • Angino A.
      • Martini F.
      • Borbotti M.
      • Scognamiglio A.
      • Simoni M.
      • Silvi P.
      • Di Pede F.
      • Carrozzi L.
      • Porta D.
      • Simonato L.
      • Crispo A.
      • Merletti F.
      • Forastiere F.
      Fumo e patologie respiratorie: le carte del rischio per BPCO e tumore al polmone. Smoking and respiratory disease: risk cards for COPD and lung cancer.
      ]. In general, 81% of the patients who came to the PUs with a diagnosis of CRD (n = 501) received confirmation that they had CRD.
      Table 1General characteristics of the patients referred to the Hospital Pulmonary Unit (PU).
      Referred to the PU (n = 701) validNot referred to the PU (n = 5640) validp
      By chi square test.
      Age, mean ± SD, [median], range59 ± 15 [62] 15-8956 ± 16 [57] 10-99<0.001
      By non-parametric test U of Mann-Whitney.
      Gender
       males50.645.30.008
       Females49.454.7
      BMI, mean ± SD, [median], range obesity, n28 ± 5 [28] 17–51 66.1
      Smoking habit
       current28.517.1<0.001
       ex26.923.10.03
       never44.759.8<0.001
      Current work31.840.1<0.001
      Occupational exposure to dust47.526.0<0.001
      Educational level (years)
       ≤861.452.1<0.001
       9-1330.035.00.01
       >138.612.90.002
      a By chi square test.
      b By non-parametric test U of Mann-Whitney.
      Table 2Symptoms/diseases self-reported by the patients referred by the General Practitioner (GP) to the Hospital Pulmonary Units (PU) (n = 701).
      N (%)
      Reported respiratory symptoms
       usual
      For most days a week for at least 3 months a year apart from common cold/flu.
      cough
      221 (31.5)
       usual
      For most days a week for at least 3 months a year apart from common cold/flu.
      phlegm
      175 (25.8)
       current
      Past twelve months; COPD, chronic obstructive pulmonary disease.
      wheeze
      371 (52.9)
       dyspnea247 (35.2)
      Reported medical diagnosis
       emphysema69 (9.8)
       ever asthma169 (24.1)
       current asthma131 (18.7)
       ever tuberculosis11 (1.6)
       ever pneumonia148 (21.1)
       current pneumonia7 (1.0)
       ever rhinitis123 (17.5)
       current rhinitis108 (15.4)
      GP diagnosis
       Any respiratory disease501 (71.5)
       Asthma162 (23.1)
       Chronic Bronchitis128 (18.3)
       COPD127 (18.1)
       Rhinitis130 (18.5)
      a For most days a week for at least 3 months a year apart from common cold/flu.
      b Past twelve months; COPD, chronic obstructive pulmonary disease.
      Correctly diagnosed COPD was found in 52/128 patients (sensitivity, 40.6%), whereas the absence of COPD was correctly identified in 498/573 (specificity, 86.9%); the disease was undiagnosed in 76/128 subjects (59.4%), and over-diagnosed in 75/573 (13.1%).
      Presence and absence of COPD (absolute agreement) were correctly identified in 78% of the cases; the agreement between GPs and pulmonologists, as indicated by kappa, was fair (kappa = 0.28, 95% CI 0.20–0.35) (Table 3). The agreement was slightly better, ranging from fair to moderate, when the pulmonologists used the LLN criterion for the COPD diagnosis (kappa = 0.35, 95% CI 0.16–0.55). In sensitive analyses by sex, the agreement was higher in males k = 0.32) than females (k = 0.19).
      Table 3Agreement between general practitioners (GP) and pulmonologists (gold standard) as regards the diagnosis of chronic obstructive pulmonary disease (COPD).
      Sensitivity, % (95% CI)40.62 (32.04–49.66)
      Specificity, % (95% CI)86.91 (83.87–89.56)
      Positive Likelihood ratio (95% CI)3.10 (2.31–4.18)
      Negative Likelihood ratio (95% CI)0.68 (0.59–0.79)
      Positive predictive value, % (95% CI)40.94 (32.30–50.02)
      Negative predictive value, % (95% CI)86.76 (83.71–89.42)
      Absolute agreement, %78.46
      Kappa (95% CI)0.28 (0.20–0.35)
      95% CI: 95% confidence interval.
      Several significant differences were found among the four groups as outlined by the comparison between GPs and pulmonologists (Table 4). The patients with correctly diagnosed COPD were older than those with undiagnosed COPD (p = 0.001), and the patients with no COPD were the youngest (p ≤ 0.001). The prevalence of male gender was higher in correctly diagnosed/undiagnosed COPD than in over-diagnosed/no COPD (p ranging from <0.001 to 0.02). The frequency of current/ex smoking was lower in no COPD than in other three groups (p ranging from <0.001 to 0.05), and higher in correctly diagnosed COPD than in over-diagnosed COPD (p = 0.02). Spirometry was more frequent in correctly diagnosed and over-diagnosed COPD than in undiagnosed or in no COPD (p < 0.001).
      Table 4Characteristics of the patients by group. The groups are defined on the basis of General Practitioners' (GPs) diagnosis of COPD compared to the reference standard (Pulmonologists).
      COPD correctly diagnosed n = 52COPD undiagnosed n = 76COPD over-diagnosed n = 75no COPD n = 498
      Age: mean (SD), years69.7 (7.9)67.4 (12.2)66.0 (11.2)55.4 (15.5)
      Sex, male: female ratio38:1450:2635:40232:266
      Current/ex-smoker, %39 (81.3)51 (70.8)44 (62.0)239 (49.5)
      Obesity, %37 (71.2)47 (63.5)42 (56.8)323 (67.4)
      Previous spirometry,%29 (55.8)19 (25.7)41 (54.7)123 (25.2)
      In multivariate models, compared to no COPD, the risk factors for under-diagnosis were the age>62 years (OR 3.00, 1.73–5.22) and current/ex smoking (OR 2.38, 1.30–4.37) (Table 5). Compared to correctly diagnosed COPD, the age>62 years decreased the risk of both over-diagnosed (OR 0.25, 95% CI 0.09–0.72) and undiagnosed COPD (OR 0.28, 95% CI 0.10–0.81). Still compared to correctly diagnosed COPD, performing previous spirometry decreased the risk for undiagnosed COPD by about 3.6 folds (OR 0.25, 0.11–0.59); after including in the analysis self-reported symptoms, co-presence of chronic cough, phlegm, and dyspnea (versus chronic cough or phlegm without dyspnea) decreased the risk for undiagnosed COPD of about 4 folds (OR 0.25, 0.11–0.59). Other factors, such as occupational exposure or educational level did not seem to affect the accuracy of COPD diagnosis.
      Table 5Association between patient's characteristics and accuracy of COPD diagnosis. Odds ratio (OR) and 95% Confidence Intervals (CI).
      Under-diagnosed COPD Vs. no COPDOver-diagnosed COPD vs correctly diagnosed COPDUndiagnosed COPD vs correctly diagnosed COPD
      crude OR (95% CI)crude OR (95% CI)crude OR (95% CI)
      Age > 62 years3.23 (1.93–5.41)***0.38 (0.15–0.96)*0.34 (0.13–0.86)*
      Female sex0.45 (0.27–0.75)**3.11 (1.45–6.65)**1.41 (0.65–3.06)
      Current/ex-smoker2.48 (1.45–4.25)**0.38 (0.16–0.90)*0.56 (0.23–1.36)
      Obesity0.84 (0.50–1.40)0.53 (0.25–1.13)0.71 (0.33–1.51)
      Previous spirometry1.03 (0.59–1.80)0.96 (0.47–1.95)0.27 (0.13–0.58)**
      adjusted OR (95% CI)adjusted OR (95% CI)adjusted OR (95% CI)
      Age > 62 years3.00 (1.73–5.22)***0.25 (0.09–0.72)*0.28 (0.10–0.81)*
      Female sex0.66 (0.37–1.18)2.09 (0.88–4.94)1.08 (0.44–2.70)
      Current/ex-smoker2.38 (1.30–4.37)**0.41 (0.15–1.10)bl0.74 (0.27–2.04)
      Obesity0.77 (0.44–1.34)0.63 (0.26–1.50)0.52 (0.21–1.31)
      Previous spirometry0.91 (0.49–1.68)0.91 (0.41–2.04)0.25 (0.11–0.59)**
      95% CI: 95% confidence interval.
      *p < 0.05; **p < 0.01; ***p < 0.001.
      Bl borderline significant: 0.5 < p < 1.

      4. Discussion

      GPs in this study were satisfactorily good in correctly excluding the patients who did not have COPD (specificity 87%), but poor in diagnosing the patients with COPD (sensitivity 41%). The positive likelihood ratio greater than 2, but lower than 5 (Table 3), indicates that the positive diagnosis made by GPs can be taken into account, but it is not of clinical relevance. In our study, age, smoking status and performing diagnostic tests were confirmed as the most important factors for a more successful screening of at-risk individuals.
      We did not encounter studies directly assessing diagnostic concordance between GP and pulmonologists, even if many researches assessed diagnostic accuracy of prior GP diagnosis by comparison to spirometry [
      • Casas Herrera A.
      • Montes de Oca M.
      • Lopez Varela M.V.
      • Aguirre C.
      • Schiavi E.
      • Jardim J.R.
      • Team P.
      COPD underdiagnosis and misdiagnosis in a high-risk primary care population in four Latin American Countries. A key to enhance disease diagnosis: the PUMA study.
      ]. In general, despite the methodological heterogeneity, most of the studies observed that the accuracy of respiratory diagnoses including the one of COPD made by GPs in primary health care is low and mistakes in the diagnosis are characterized by both under and over-diagnosis [
      • Jose B.P.
      • Camargos P.A.
      • Cruz Filho A.A.
      • Correa Rde A.
      Diagnostic accuracy of respiratory diseases in primary health units.
      ]. Overall, we found that the agreement between GPs and pulmonologists was fair. In general, 81% of the patients who came to the PUs with a diagnosis of CRD (n = 501) received confirmation that they were suffering from asthma, COPD, chronic bronchitis, pneumonia or rhinitis.
      In the case of COPD, GPs were more concordant when the diagnoses were made at PU using the ATS/ERS LLN criterion instead of the GOLD fixed ratio. Since the FEV1 decreases more quickly with age than the FVC, the GOLD definition might tend to over diagnose COPD in the elderly. For this reason, some authors suggested using the LLN criterion that is based on age stratified values of FEV1/FVC ratio [
      • Bhatt N.Y.
      • Wood K.L.
      What defines abnormal lung function in older adults with chronic obstructive pulmonary disease?.
      ,
      • Hwang Y.I.
      • Kim C.H.
      • Kang H.R.
      • Shin T.
      • Park S.M.
      • Jang S.H.
      • Park Y.B.
      • Kim C.H.
      • Kim D.G.
      • Lee M.G.
      • Hyun I.G.
      • Jung K.S.
      Comparison of the prevalence of chronic obstructive pulmonary disease diagnosed by lower limit of normal and fixed ratio criteria.
      ]. In our study, where ¾ of the population was older than 50 years, the prevalence of correctly diagnosed COPD was higher, as a trend for patients diagnosed with LLN criterion than those diagnosed with the GOLD criterion (12% vs 7%, p = 0.09).
      We found that over-diagnosed COPD was relatively low (13.1%) in comparison to other studies using spirometry; this seems to be related to the low propensity to diagnose COPD by GPs. A recent review found the lack of precision for the diagnosis of COPD ranged from 28% to 40% for over-diagnosis [
      • Jose B.P.
      • Camargos P.A.
      • Cruz Filho A.A.
      • Correa Rde A.
      Diagnostic accuracy of respiratory diseases in primary health units.
      ]. In Australia, among patients with COPD diagnosis made by GPs, confirmation of COPD was not present in 31% [
      • Walters J.A.
      • Walters E.H.
      • Nelson M.
      • Robinson A.
      • Scott J.
      • Turner P.
      • Wood-Baker R.
      Factors associated with misdiagnosis of COPD in primary care.
      ]. In Greece, 49.8% of patients with primary diagnosis of COPD did not meet the GOLD criterion for COPD [
      • Sichletidis L.
      • Chloros D.
      • Spyratos D.
      • Chatzidimitriou N.
      • Chatziiliadis P.
      • Protopappas N.
      • Charalambidou O.
      • Pelagidou D.
      • Zarvalis E.
      • Patakas D.
      The validity of the diagnosis of chronic obstructive pulmonary disease in general practice.
      ]. In UK, out of patients with a primary care diagnosis of COPD, 20% had spirometry inconsistent with COPD [
      • Strong M.
      • Green A.
      • Goyder E.
      • Miles G.
      • Lee A.C.
      • Basran G.
      • Cooke J.
      Accuracy of diagnosis and classification of COPD in primary and specialist nurse-led respiratory care in Rotherham, UK: a cross-sectional study.
      ]. In our study, the patients with over-diagnosed COPD received at PUs a diagnosis of “simple” chronic bronchitis in 57.9% of cases and of asthma in 29.4%. Diagnostic confusion between COPD and asthma appears common [
      • Tinkelman D.G.
      • Price D.B.
      • Nordyke R.J.
      • Halbert R.J.
      Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over.
      ]. Also a multicenter study involving 24 Italian pulmonary or geriatric institutions concluded that asthma in the elderly is frequently confused with COPD, and misdiagnosis can be related to older age and to greater degree of disability [
      • Bellia V.
      • Battaglia S.
      • Catalano F.
      • Scichilone N.
      • Incalzi R.A.
      • Imperiale C.
      • Rengo F.
      Aging and disability affect misdiagnosis of COPD in elderly asthmatics: the SARA study.
      ]. As above reported, implementing LLN criterion instead of the fixed ratio of FEV1/FVC may reduce the risk of over-diagnosis of COPD in elderly people. In a study performed in Korea, the prevalence of COPD was 10.9% by LLN criterion and 15.5% by the fixed ratio of FEV1/FVC among subjects older than 45 years, and in subjects with age ≥65, 14.9% and 31.1%, respectively [
      • Hwang Y.I.
      • Kim C.H.
      • Kang H.R.
      • Shin T.
      • Park S.M.
      • Jang S.H.
      • Park Y.B.
      • Kim C.H.
      • Kim D.G.
      • Lee M.G.
      • Hyun I.G.
      • Jung K.S.
      Comparison of the prevalence of chronic obstructive pulmonary disease diagnosed by lower limit of normal and fixed ratio criteria.
      ]. In our study, we did not find significant difference in the prevalence of over-diagnosed COPD between the two criteria.
      The high frequency of undiagnosed COPD (59.4%) in our study is relatively surprising. We confirmed the results of the most part of studies concerning the under-diagnosis of COPD. In a study performed in four Latin American Countries, irrespective of the spirometric definition used, COPD under-diagnosis was a major health problem in the primary care setting; under-diagnosis was 77% and 73% using the GOLD criterion and the LLN criterion, respectively [
      • Casas Herrera A.
      • Montes de Oca M.
      • Lopez Varela M.V.
      • Aguirre C.
      • Schiavi E.
      • Jardim J.R.
      • Team P.
      COPD underdiagnosis and misdiagnosis in a high-risk primary care population in four Latin American Countries. A key to enhance disease diagnosis: the PUMA study.
      ]. Josè et al. in their review of literature, found that under-diagnosis ranged from 26% to even 81% [
      • Jose B.P.
      • Camargos P.A.
      • Cruz Filho A.A.
      • Correa Rde A.
      Diagnostic accuracy of respiratory diseases in primary health units.
      ]. Data from the international BOLD Study, the Latin American Platino Study, the Spanish EPI-SCAN, and the Colombian PRECOL overall found that 81.4% of COPD cases were undiagnosed [
      • Bernd L.
      • Joan B.S.
      • Michael S.
      • Bernhard K.
      • Lowie E.V.
      • Louisa G.
      • Peter B.
      • Marc M.
      • Francisco G.R.
      • Kaveh A.
      • Julio A.
      • Ana M.M.
      • Rogelio P.P.
      • Maria M.O.
      • Carlos A.T.
      • Andres C.
      • Mauricio G.G.
      • Sonia B.
      Bold Collaborative Research Group tEPISTtPT, the PSG. Determinants of underdiagnosis of COPD in national and international surveys.
      ]. In agreement with this study, we found that under-diagnosis of COPD was associated with younger age and no previous spirometry. Previously, a Brazilian study reported an under-diagnosis rate of COPD of 71.4% [
      • Queiroz M.C.
      • Moreira M.A.
      • Rabahi M.F.
      Underdiagnosis of COPD at primary health care clinics in the city of Aparecida de Goiania, Brazil.
      ].
      About 40% of the patient with COPD were correctly diagnosed by GPs in our study. As other authors had observed [
      • Pellegrino R.
      • Viegi G.
      • Brusasco V.
      • Crapo R.O.
      • Burgos F.
      • Casaburi R.
      • Coates A.
      • van der Grinten C.P.
      • Gustafsson P.
      • Hankinson J.
      • Jensen R.
      • Johnson D.C.
      • MacIntyre N.
      • McKay R.
      • Miller M.R.
      • Navajas D.
      • Pedersen O.F.
      • Wanger J.
      Interpretative strategies for lung function tests.
      ,
      • Tinkelman D.G.
      • Price D.B.
      • Nordyke R.J.
      • Halbert R.J.
      Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over.
      ], we also found that correctly diagnosed COPD was more prevalent in subjects with previous spirometry (14% vs 5%, p < 0.001). Actually, the literature has shown that delayed or erroneous diagnosis of respiratory conditions may be common in primary care due to underuse of spirometry or poor spirometric technique [
      • Joo M.J.
      • Au D.H.
      • Fitzgibbon M.L.
      • McKell J.
      • Lee T.A.
      Determinants of spirometry use and accuracy of COPD diagnosis in primary care.
      ]. It was evidenced that clinicians use spirometry more often among patients with symptoms suggestive of COPD but less often among patients with current or past tobacco use [
      • Joo M.J.
      • Au D.H.
      • Fitzgibbon M.L.
      • McKell J.
      • Lee T.A.
      Determinants of spirometry use and accuracy of COPD diagnosis in primary care.
      ]. We found that one in four undiagnosed patients performed prior spirometry, whereas more than half of correctly diagnosed COPD (56%) did. Quite surprisingly, the prevalence of prior spirometry was reported more frequently also in over-diagnosed COPD (55%). On the other hand, an Australian study found that having a spirometer in the general practice was not predictive of agreement between clinical and spirometric diagnoses [
      • Zwar N.A.
      • Marks G.B.
      • Hermiz O.
      • Middleton S.
      • Comino E.J.
      • Hasan I.
      • Vagholkar S.
      • Wilson S.F.
      Predictors of accuracy of diagnosis of chronic obstructive pulmonary disease in general practice.
      ].
      Hill et al. [
      • Hill K.
      • Goldstein R.S.
      • Guyatt G.H.
      • Blouin M.
      • Tan W.C.
      • Davis L.L.
      • Heels-Ansdell D.M.
      • Erak M.
      • Bragaglia P.J.
      • Tamari I.E.
      • Hodder R.
      • Stanbrook M.B.
      Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care.
      ] evaluated the accuracy of prior diagnosis or non-diagnosis of COPD and identified associated clinical characteristics in Canadian patients from primary care. They reported the absence of distinguishing clinical characteristics within the patients with correctly diagnosed and misdiagnosed COPD. On opposite, we found several differences within the studied groups as regard to age, sex and smoking habit. Strong et al. in their cross-sectional study, by multivariate analyses found that to be male was positively associated with agreement between the primary diagnosis of COPD and the spirometry at the Breathing Space diagnosis [
      • Strong M.
      • Green A.
      • Goyder E.
      • Miles G.
      • Lee A.C.
      • Basran G.
      • Cooke J.
      Accuracy of diagnosis and classification of COPD in primary and specialist nurse-led respiratory care in Rotherham, UK: a cross-sectional study.
      ]. Accordingly, we found that the female gender was related to higher risk of both under-diagnosis and over-diagnosis, although insignificantly, when compared to correctly diagnosed COPD. This might explain the agreement was higher for males than females.
      Our study presents some limitations but also strengths. As a strength, the methodology was standardized and harmonized. In addition, the study was spread in all Italy. As a limitation, there is the fact that our findings are not representative at the national level. Unfortunately, the national dimension could not be taken into account in the analysis.

      5. Conclusion

      Results from the pan-national E-DIAL study confirm that COPD under-diagnosis is a major problem in primary care, which suggests a need for greater screening of at-risk individuals. It is necessary to enhance COPD diagnosis and to reduce misdiagnosis by using an appropriate methodology. Professional education and internal and external audits seem advisable to improve COPD management in Italy.

      Acknowledgements

      The authors are indebted to the patients and to the GPs that recruited them. They also thanks Alberto Visconti that helped in the study conduction. Unrestricted educational grant of Menarini Industrie Farmaceutiche Riunite.
      Members of the E-DIAL Study Group are as follows:
      • CONTI Paolo, POCHETTI Patrizia, 002 Ospedale Sant'Andrea, Corso Mario Abbiate, 21 13100 VERCELLI
      • OCCHIONERO Lucia, MASTINU Alessandro, 003 Ospedale Cardinal Massaia Corso Dante, 202 14100 ASTI
      • TUBALDI Alberto, RICCIONI Giordano, 005, Ospedale Generale Provinciale Macerata Area vasta 3 ASUR Regione Marche Via Santa Lucia 2–62100 Macerata 62100 MACERATA
      • FABIANO Franco, CORDANI Stefano, 006, ASL 5 – Spezzino Ospedale S. Andrea, stabilimento Felettino Via del Forno n.5–19125 La Spezia
      • BENAMATI Giulio (dal 1/4/2011), BASSETTI Sergio (in pensione dal 12/3), 007, Ospedale alto Garda e Ledro - Ospedale Civile Via Capitelli, 48 38062 ARCO (TN)
      • MANDURINO Luciano, GIURGOLA Sergio, 008, Ospedale Sacro Cuore di Gesù, Strada Provinciale per Alezio 73014 GALLIPOLI (LE)
      • TOGNELLA Silvia, BERTACCO Stefano, 009, ULSS22 Regione Veneto Ospedale Orlandi-Bussolengo-Verona, Via Ospedale, 2 37012 BUSSOLENGO (VR)
      • MAZZA Francesco, MANGANELLO Gianluca, 010, A.O. Santa Maria degli Angeli Via Montereale, 24 33170 PORDENONE
      • CANDOLI Piero, MESSI Alessandro, 011, Presidio Ospedaliero di Lugo Azienda Ospedaliera di Ravenna Viale Dante, 10 48022 LUGO (RA)
      • VINCENTI Rigoletta, PORCU Anna, 012, Ospedale di Carrara ASL1 Piazza Sacco e Vanzetti 54033 CARRARA (MS)
      • DI TOMASSI Maurizio, CANNETI Elena, 013, Ospedale “Misericordia” Via Senese 104 58100 GROSSETO
      • ALLERI Pietro, BRUNI Bruno, 014, Centro Servizi Grocco Via della Pallotta, 42 - Piano −1 06126 PERUGIA
      • REALE Giuseppe, D’ANDREA Nadia, 015, A.C.O. San Filippo Neri, Via G. Martinotti, 20 00135 ROMA
      • PISTELLI Riccardo, BERARDINI Ludovica, Complesso Integrato Columbus Via Moscati 31, 016 00168 ROMA
      • DE BENEDETTO Fernando, D'INTINO Domenico, 017, ASL 02 Lanciano-Vasto-Chieti Ospedale Clinicizzato SS. Annunziata Via dei Vestini 66100 CHIETI
      • SANDUZZI ZAMPARELLI Alessandro, PONTICELLO Antonio, 018, A. O.R.N. Monaldi-Cotugno-CTO Piazza Ettore Ruggieri 80131 NAPOLI
      • ZAMPARELLI Paolo, CUTAJAR MARINA, 019, P.O. Santa Maria della Misericordia Corso Italia, 1 80067 SORRENTO (NA)
      • TORALDO Domenico Maurizio, MELELEO Fausto, 020, III Pneumologia Stabilimento Ospedaliero A. Galateo Via Croce di Lecce 73016 SAN CESARIO DI LECCE (LE)
      • MORETTI Anna Maria, DI GIOIA Giuseppe, 021, A.O. Universitaria Policlinico Piazza Giulio Cesare, 11 70124 BARI
      • GALLELLI Andrea, VERO Giuseppe, 022, A.O. Policlinico "Mater Domini" Campus Universitario Salvatore Venuta - Viale Europa88100 Germaneto - CATANZARO
      • PENNISI Alfio, PORTO GIOVANNI, 023, Casa di Cura Musumeci-Gecas Via dell'Autonomia, 57 95030 GRAVINA DI CATANIA (CT)
      • MARRONE Antonino, PERALTA GIUSEPPE, 024, Presidio Ospedaliero Sant'Antonio Abate Via Cosenza, 82
      • PIRINA Pietro, FOIS Alessandro, 025, Azienda Ospedaliero Universitaria di Sassari Viale San Pietro nuovo edificio scala C 1° piano 07100 SASSARI

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