ABSTRACT
Background:
The prevalence and healthcare burden of COPD are estimated to arise over the next years not only due to persistent tobacco consumption but also due to misdiagnosis of the disease. The present observational study among smokers and ex-smokers aims to assess the prevalence of COPD misdiagnosis (over and underdiagnosis) as well as the differences and similarities between patients with previous correct diagnosis of COPD and those with underdiagnosed disease.
Materials and Methods:
We performed an observational cross-sectional study in four rural counties and in one of the primary health centers of the metropolitan city of Thessaloniki, Greece aiming estimate the prevalence of COPD and evaluate the differences between patients with diagnosed and underdiagnosed disease.
Results:
Overall, 5,239 participants were enrolled in the study, of whom 565 subjects (10.8%) fulfilled the clinical and spirometric criteria for the diagnosis of COPD according to GOLD guidelines. Notably, 264 patients had a previous correct diagnosis of COPD (46.7%), 301 patients were underdiagnosed (new cases) while 461 subjects had a previous false diagnosis of COPD (overdiagnosis). Patients with underdiagnosed COPD were younger and more frequently current smokers. In addition, they presented less frequently with clinically important respiratory symptoms estimated by specific questionnaires but on the contrary the percentages of single symptoms such as cough, phlegm, dyspnea and wheezing were not significantly different compared with those with correct prior COPD diagnosis. They also reported fewer comorbidities and they mostly had early-stage disease based on spirometry or medical history.
Conclusion:
There is a noteworthy number of underdiagnosed and overdiagnosed cases of COPD among an unselected sample of the general population in northern Greece. Underdiagnosed patients with COPD are younger, usually current smokers but with early-stage disease compared with previously diagnosed subjects. National screening programs for high risk populations (current smokers with respiratory symptoms) in the primary care setting as well as GPs training on spirometry and COPD management should be planed as healthcare strategies in the near future.
Keywords: COPD, diagnosed COPD, primary care, underdiagnosed COPD
Introduction
Chronic Obstructive Pulmonary Disease refers to a group of respiratory diseases (chronic bronchitis/bronchiolitis and emphysema) that cause irreversible airflow limitation.[1] Even though COPD is both preventable and treatable, it constitutes the third leading cause of death worldwide, accounting for 3.23 million deaths in the year 2019.[1] COPD classification and severity are based on the evaluation of the patient’s symptoms, the history of exacerbations, the results of pulmonary function tests and the presence of comorbidities.[2]
The prevalence and burden of COPD are estimated to arise over the next years not only due to persistent tobacco consumption but also due to underdiagnosis and false diagnosis of the disease.[3] Underuse of spirometry due to socioeconomic factors or lack of time/competence of General Practitioners play a key role in the underdiagnosis of the disease, whereas population-related parameters such as lower education level, ethnic minority background, or underestimation of symptoms also contribute to it.[4]
On the other hand, the main cause of overdiagnosis of COPD remains the lack of expertise in the performance and the interpretation of spirometry as well as the coexistence of medical conditions whose clinical symptoms are similar to COPD (asthma, congestive heart failure).[4,5] In the BOLD study the percentage of false positive COPD (unobstructed postbronchodilator spirometry), among patients with a previous medical diagnosis of COPD, was 55.3% (FEV1/FVC >0.7) or 61.9% (FEV1/FVC >LLN).[6] We should emphasize that misdiagnosis is usually associated with overtreatment, and about a third of overdiagnosed subjects are prescribed inhaled medication for daily use (most commonly LABA/ICS).[6] On the contrary the percentage of COPD underdiagnosis may be as high as 77-83.6%, even in high income countries.[7,8] In this case undertreatment or even no treatment results in more exacerbations and disease progression, thus increasing morbidity and mortality rates.[9]
COPD remains a considerable health problem in Greece affecting a notable number of individuals.[10] Even though diagnosis and treatment are based on the updated GOLD and national[11] guidelines, COPD is not usually successfully diagnosed by primary healthcare professionals due to lack of adequate training in respiratory medicine.
The present observational study among an unselected sample of smokers and ex-smokers in the general population of northern Greece aims to assess the prevalence of COPD misdiagnosis (over and underdiagnosis) as well as the differences between patients with previous correct diagnosis of COPD and those with underdiagnosed disease.
Materials and Methods
Study design
We performed an observational cross-sectional study in four rural counties and in one of the primary health centers of the metropolitan city of Thessaloniki, Greece aiming to estimate the prevalence of COPD and evaluate the differences between patients with diagnosed and underdiagnosed disease. The study was conducted by pulmonologists from the Pulmonary Department of Aristotle University of Thessaloniki and was supervised by the 3rd Regional Health Care Authority of Greece. It was part of a COPD screening/smoking cessation program of the 3rd Regional Health Care Authority of Greece and took place from 1/1/2012 to 31/12/20** at five primary health care centers. Participants were urged to enroll via a quit-smoking campaign that focused on the early detection of COPD in a reference population of about 500,000 residents. Individuals who were interested in taking part in the program booked an appointment at the nearest primary care center, where they were examined by pulmonologists after written consent was granted. A complete medical history was recorded upon registration.
All participants had a medical advice about the advantages of smoking cessation of 5-10 minutes and for those who were interested, an appointment in the smoking cessation clinic of G. Papanikolaou Hospital, Thessaloniki, Greece was arranged. There was psychological and medical support for smoking cessation, free pass to public transportation to approach the hospital and a 24-hour support telephone line.
Selection of study subjects – inclusion/exclusion criteria
Eligible subjects were those aged 40 years or older, current or former smokers, with a smoking history of at least 10 pack-years. Previous diagnosis of COPD, regular or occasional use of inhalers, or the persistence of respiratory symptoms were inclusion criteria. People who reported a history of other respiratory diseases such as bronchial asthma, bronchiectasis, lung cancer, tuberculosis, or interstitial lung disease, were excluded from the study. We excluded patients with asthma because in this case a clear indication for treatment with inhaled drugs may lead to normal spirometry, whereas the same scenario is compatible with COPD overdiagnosis.
Data collection – measurements
All participants of the study performed acceptable spirometry tests (according to the ERS/ATS official standards) before and 15–30 min after inhalation of 400 μg of salbutamol, under the supervision of a pulmonologist. Thereafter, pulmonary function test measurements were analyzed to determine whether the diagnosis of COPD could be established. In this case, each patient was further classified into GOLD A to E groups based on the mMRC dyspnea scale and CAT score, the number of exacerbations during the last year and their comorbidities.
Variables and definitions
Diagnosis of COPD was based on compatible symptoms plus post bronchodilation fixed cut-off ratio (FEV1/FVC < 0.7). COPD patients were further categorized based on airflow limitation (GOLD 1: FEV1 ≥ 80%pred., 2: 80 < FEV1 ≥ 50%pred., 3: 50 < FEV1 ≥ 30%pred. and 4: <30%pred.) and clinical disease severity according to exacerbations history during the last year and symptoms [we used the worst score of mMRC (0-1 and ≥2) or CAT (<10 and ≥10) to GOLD A (mMRC: 0-1 or CAT <10 and 0-1 moderate exacerbations), B (mMRC ≥2 or CAT ≥10 and 0-1 moderate exacerbations) and Ε (≥2 moderate exacerbations or ≥1 hospitalization) subgroups.
Under-diagnosis was defined as the presence of clinical and spirometric criteria of COPD (present study) but no medical history of the disease.
Conversely, over-diagnosis was defined as the presence of normal spirometry (pre and post FEV1/FVC >0.7, FVC and FEV1 >80% of predicted values) and a previous medical diagnosis of COPD with prescription of inhaled drugs for at least 12 consecutive months during the last 5 years, based on data from the national electronic prescription system. Participants with a restrictive spirometric pattern were referred for further examination and were excluded from the statistical analysis.
We defined overtreatment as the prescription of any drug in participants without obstructive pattern and the prescription of an inappropriate combination of inhaled drugs in patients with COPD, according to the updated GOLD strategy document treatment guidelines.
We used descriptive statistics to calculate COPD prevalence (previously correct and newly diagnosed cases) and the prevalence of false positive diagnosis. Parametric (t-test) and nonparametric (Wilcoxon Signed Rank, Kruskal–Wallis) tests were used to compare participants with or without COPD and those with prior correct diagnosis of the disease versus undiagnosed patients. All statistical analyses were conducted using the IBM SPSS 23.0 statistical package.
Medical ethics
All participants gave written informed consent and authorization to pulmonologists of the screening program to access the national electronic system and search for repeated prescribed inhaled drugs at least 12 consecutive months during the last 5 years. The study protocol has been reviewed and approved by the Scientific and Medical Ethics Committee of “G. Papanikolaou” General Hospital in Thessaloniki.
Results
Overall, 5,239 participants were enrolled in the study, 3,206 (61.2%) were males. The median age of the participants was 57 years (IQR: 48-68), the median number of pack-years was 25 (IQR: 13-45) and the percentage of current smokers was 55.8%.
A total of 565 subjects (10.8%) fulfilled the clinical and spirometric criteria for COPD according to the updated GOLD guidelines. Notably, 264 patients had a previous medical diagnosis of COPD (46.7% of COPD patients), 301 were underdiagnosed (new cases) while 461 subjects had a previous incorrect medical diagnosis of COPD (overdiagnosis). Demographic, spirometric, respiratory symptoms and comorbidities data of COPD and non-COPD participants are shown in Table 1.
Table 1.
Comparison of clinical and spirometric parameters between COPD and non-COPD participants
| Parameters | Non-COPD n=4,674 | COPD n=565 | P |
|---|---|---|---|
| Age | 56±12.5 years | 67±11.4 years | P<0.01 |
| Gender (males) | 2,763 (59.1%) | 443 (78.4%) | P<0.01 |
| BMI | 28.51±5.43 | 27.77±5.04 | P<0.01 |
| Current smokers | 2,606 (55.8%) | 318 (56.3%) | P>0.01 |
| Pack-years (current) | 30±23.88 | 45.5±34.8 | P<0.01 |
| Pack-years (ex-smokers) | 13±29.18 | 45±46.3 | P<0.01 |
| Respiratory symptoms | |||
| 1. Cough | 431 (9.2%) | 318 (56.3%) | P<0.01 |
| 2. Phlegm | 467 (10%) | 314 (55.6%) | P<0.01 |
| 3. Dyspnea | 264 (5.6%) | 332 (58.8%) | P<0.01 |
| 4. Wheezing | 160 (3.4%) | 169 (29.9%) | P<0.01 |
| Comorbidities (yes) | |||
| 1. Coronary heart disease | 212 (4.5%) | 117 (20.7%) | P<0.01 |
| 2. Stroke | 36 (0.8%) | 15 (2.7%) | P<0.01 |
| 3. Arterial hypertension | 592 (12.7%) | 207 (36.6%) | P<0.01 |
| 4. Diabetes | 220 (4.7%) | 74 (13.1%) | P<0.01 |
| 5. Hyperlipidemia | 523 (11.2%) | 112 (19.8%) | P<0.01 |
| 6. Depression | 100 (2.1%) | 38 (6.7%) | P<0.01 |
| Pulmonary function tests | |||
| Post FEV1%pred. | 96.98±16.41% | 67.26±18.9% | P<0.01 |
| Post FVC %pred. | 96.33±17.38% | 84.67±21.2% | P<0.01 |
| post FEV1/FVC % | 81.6±11.61% | 64±7.19% | P<0.01 |
| Post MMEF %pred. | 86.95±30.49% | 38.8±13.3% | P<0.01 |
FEV1: forced expiratory volume in the 1st second, FVC: forced vital capacity, MMEF: maximal mid expiratory flow
Patients with a prior correct COPD diagnosis who were already treated with either short or long-acting inhaled bronchodilators or bronchodilators plus inhaled corticosteroids were 262/264 (99.2%, short-acting bronchodilators: 4.5%, long-acting bronchodilators: 28.4%, long-acting bronchodilators + ICS: 66.3%). Based on the severity of the disease, 196 (74.2%) of them should have been treated only with long-acting bronchodilators (GOLD A + B), whereas 187 patients (70.8%) were treated inadequately with short-acting bronchodilators or long-acting bronchodilators plus inhaled corticosteroids. On the contrary, 275/301 (91.4%) of underdiagnosed COPD patients had no regular prescription of inhaled drugs t and only 26 of them (8.6%) were treated occasionally by either short-acting inhaled bronchodilators or long-acting bronchodilators plus inhaled corticosteroids. Moreover, 458/461 (99.3%) of overdiagnosed COPD subjects had been prescribed inhaled medication, while the majority of them (319/461, 69.2%) used regularly long-acting bronchodilators plus inhaled corticosteroids. Individuals with overdiagnosis of COPD were urged to stop the inhaled treatment, while over or wrongly-treated patients with COPD switched to another drug.
Comparison between patients with prior correct medical COPD diagnosis and those with an underdiagnosed disease was conducted to investigate the differences in COPD stages, respiratory symptoms, pulmonary function tests and the use of inhaled medication [Table 2]. Patients with underdiagnosed COPD were younger, more frequently current smokers but with a similar smoking burden compared with those who were already diagnosed. In addition, they presented less frequently with clinically important respiratory symptoms (% with MRC > 1 or CAT score ≥10) but the presence of single symptoms such as cough, phlegm, dyspnea and wheezing was not significantly different compared with the group that had a correct prior COPD diagnosis. They also reported fewer comorbidities and they mostly had early-stage disease based on spirometry (GOLD stages 1-4) or clinical disease severity.
Table 2.
Comparison of clinical parameters and severity status between diagnosed and underdiagnosed COPD patients
| Parameters | COPD prior correct diagnosis n=264 | COPD underdiagnosis n=301 | P |
|---|---|---|---|
| Age | 72±10.48 | 62±10.89 | P<0.01 |
| Gender (males) | 226 (85,6%) | 217 (72,1%) | P<0.01 |
| BMI | 28±4.99 | 27.75±5.07 | P<0.01 |
| Current smokers | 114 (43,2%) | 204 (62,8%) | P<0.01 |
| Pack-years | 45±42.36 | 45±38.33 | P>0.01 |
| Pack-years (current) | 45±34.23 | 51±35.93 | P<0.01 |
| Pack-years (ex-smokers) | 45.5±46.68 | 41±45.95 | P<0.01 |
| Respiratory symptoms | |||
| 1. Cough | 142 (53.8%) | 176 (51.8%) | P>0.01 |
| 2. Phlegm | 139 (52.7%) | 175 (58.1%) | P>0.01 |
| 3. Dyspnea | 153 (58%) | 179 (59.5%) | P>0.01 |
| 4. Wheezing | 78 (29.5%) | 91 (30.2%) | P>0.01 |
| MMRC | 1±0.84 | 1±0.78 | P>0.01 |
| MMRC >1 | 115 (43.6%) | 81 (26.9%) | P<0.01 |
| CAT | 12±7.37 | 8±6.8 | P<0.01 |
| CAT ≥10 | 146 (55.3%) | 128 (42.5%) | P<0.01 |
| Comorbidities (yes) | |||
| 1. Coronary heart disease | 61 (23.1%) | 56 (18.6%) | P<0.01 |
| 2. Stroke | 9 (3.4%) | 6 (2%) | P>0.01 |
| 3. Arterial hypertension | 117 (44.3%) | 90 (29.9%) | P<0.01 |
| 4. Diabetes | 40 (15.2%) | 34 (11.3%) | P>0.01 |
| 5. Hyperlipidemia | 52 (19.7%) | 60 (19.9%) | P>0.01 |
| 6. Depression | 22 (8.3%) | 16 (5.3%) | P<0.01 |
| COPD stage (spirometry) | |||
| I | 42 (15.9%) | 113 (37.5%) | P<0.01 |
| II | 152 (57.6%) | 160 (53.2%) | P<0.01 |
| III | 58 (22%) | 24 (8%) | P<0.01 |
| IV | 12 (4.5%) | 4 (1.3%) | P<0.01 |
| COPD group (clinical) | |||
| A | 83 (31.4%) | 158 (52.5%) | P<0.01 |
| B | 113 (42.8%) | 115 (38.2%) | P<0.01 |
| E | 68 (25.8%) | 28 (9.3%) | P<0.01 |
| Pulmonary function tests | |||
| Post FEV1%pred. | 60.8±18.77 | 74.21±17.13 | P<0.01 |
| Post FVC %pred. | 76.23±20.82 | 93.1±19.56 | P<0.01 |
| post FEV1/FVC % | 63±7.98 | 65.4±6.08 | P<0.01 |
| Post MMEF %pred. | 34.5±15.07 | 41.3±10.94 | P<0.01 |
| Inhaled medication | |||
| No medication | 2 | 275 (91.4%) | P<0.01 |
| Short acting bronchodilators | 12 (4.5%) | 20 (6.6%) | P<0.01 |
| Long acting bronchodilators (LAB) | 75 (28.4%) | 0 | P<0.01 |
| LAB + ICS | 175 (66.3%) | 6 | P<0.01 |
CAT: COPD assessment test (8 questions with 0-5 points each, 0-40 points total score), ICS: inhaled corticosteroids
Discussion
Main findings
Out of 5,239 participants who were enrolled in the present study, 565 (10.8%) were diagnosed with COPD according to the updated GOLD guidelines. Almost half of them (301 participants, 53.3%) reported no prior medical diagnosis of COPD (under-diagnosed) while the majority of them (490 participants, 86.7%) were not treated as proposed by GOLD guidelines (either no treatment or false treatment). In addition, a significant number of subjects (461 individuals) reported a medical diagnosis of COPD without a compatible spirometric pattern and almost all of them (99.3%) had been prescribed inhalers either occasionally or on a daily basis (overtreatment).
Patients with underdiagnosed COPD were younger, more frequently current smokers, with less severe disease and better preserved lung function.
Strengths and limitations
The strength of the present real-world study is the large number of participants and the alarming finding of underdiagnosed (untreated patients with clear indication to receive inhaled drugs) as well as overdiagnosed COPD (treated subjects with almost normal lung function). The main limitation of the study was the absence of randomization since more symptomatic subjects usually access this kind of screening programs. Underuse of spirometry in the primary care setting could explain the extremely high proportion of false positive COPD diagnosis (over-diagnosis), whereas all patients who had a previous correct COPD diagnosis had performed at least one spirometry test in the past.
Interpretation of the study results in relation to existing literature
According to the existing literature, proper diagnosis of COPD remains a challenge for physicians worldwide since a lot of individuals are still under or over-diagnosed.[12] Even though a lot of research has been done to identify the main causes of COPD misdiagnosis among different geographical regions, the estimation of the real burden of the disease has not yet been achieved.[13,14] A recent randomized study from 22 Italian primary care practices showed that 59% of COPD patients were unerdiagnosed and this statement was more frequent among younger patients (<62 years) and those without previous spirometry compared with correctly diagnosed COPD patients as observed in our study.[15] Usage of a web-based clinical decision-support system by general practitioners’ in Norway eliminated misdiagnosis cases of COPD and improved the proportion of patients who received recommendation for smoking cessation and vaccination.[16]
Most studies refer to the underuse of spirometry as the main etiological factor of COPD underdiagnosis.[3,4] It is widely noted that general practitioners (GPs) usually establish a COPD diagnosis without using pulmonary function tests since they are not adequately trained in the performance and evaluation of spirometry.[17,18] Along with the lack of access to lung function laboratories, patients who visit primary care centers are more likely to have a low socioeconomic background which leads to misinterpretation of their symptoms and postponement of early medical advice seeking.[19]
Accurate use and analysis of spirometry tests would also result in fewer cases of false diagnosis of COPD.[20] Other ways to reach a false positive diagnosis of the disease are: not performing postbronchodilation tests, including normal spirometry in the spectrum of COPD diagnosis (pre-COPD) and comorbidities such as bronchial asthma and congestive heart failure that may present with similar respiratory symptoms and fixed airway obstruction.[21] Along with that, the excessive prescription of inhaled corticosteroids in individuals with a clinical diagnosis of COPD who have mild or no airflow obstruction on spirometry tests plays an important role in the overdiagnosis and overtreatment of the disease.[22]
During the last two decades, several attempts have been made to assess the prevalence of COPD in the Greek population[10,23,24] and define the medical profile of COPD patients in the country.[24] The social and financial instability has had a remarkable impact on respiratory health issues[25] whereas the lack of early COPD detection in the primary care setting has further affected the economic burden of the disease.[26] The current situation implies the need for intense training of GPs in the early detection and appropriate treatment of the disease and indicates the importance of establishing national guidelines for primary care physicians.
Conclusion
There is a noteworthy number of underdiagnosed and overdiagnosed cases of COPD among an unselected sample of the general population in northern Greece. Underdiagnosed patients with COPD are younger, usually current smokers but with early-stage disease compared with previously diagnosed subjects. GPs training, broad use of spirometry (screening programs for high risk populations) and web-based algorithms in everyday clinical practice, especially for current/ex-smokers with respiratory symptoms (e.g., cough, phlegm, dyspnea, frequent use of antibiotics), would improve accuracy of diagnosis and lead to effective treatment strategies. The aim of national healthcare policies for COPD should be early and reliable diagnosis and management, smoking cessation and elimination of underdiagnosis, overdiagnosis and overtreatment.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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