Abstract
Challenges in the diagnostic process of chronic obstructive pulmonary disease (COPD) can result in diagnostic misclassifications, including overdiagnosis. The term “overdiagnosis” in general has been associated with variable definitions. In connection with efforts to reduce low-value care, “overdiagnosis” has been defined as a true positive diagnosis of a condition that is not associated with any harm in the diagnosed person. It is, however, unclear how the term “overdiagnosis” is used in the COPD literature. We conducted a rapid review of the literature to explore how the terms “overdiagnosis” and “misdiagnosis” are used in the context of COPD. Electronic searches of Medline were conducted from inception to October 2018, to identify primary studies that reported on over- and/or misdiagnosis of COPD using these terms. 28 articles were included in this review. Overdiagnosis and misdiagnosis in COPD were found to be used to describe five main concepts: 1) physician COPD diagnosis despite normal spirometry (14 studies); 2) discordant results for COPD diagnosis based on different spirometry-based definitions for airflow obstruction (10 studies); 3) COPD diagnosis based on pre-bronchodilator spirometry results (three studies); 4) comorbidities (e.g. heart failure or asthma) that affect spirometry and have clinical features which overlap with COPD (two studies); and 5) normalisation of abnormal (post-bronchodilator) spirometry at follow-up (one study). The terms “overdiagnosis” and “misdiagnosis” were often used interchangeably and almost always referred to a false positive diagnosis. Performing (technically correct) spirometry with correct interpretation of the results could probably reduce misdiagnosis in a large proportion of the misdiagnosed cases of COPD. In addition, guidelines need to provide a more acceptable consensus spirometric definition of airflow obstruction.
Key points
In the COPD literature, the terms “overdiagnosis” and “misdiagnosis” are often used interchangeably and almost always refer to a false positive diagnosis.
Use of spirometry with correct interpretation of the results can avoid a substantial proportion of cases of misdiagnosis of COPD.
Educational aims
To explore the use of the terms “overdiagnosis” and “misdiagnosis” in the COPD literature.
To identify the main sources of overdiagnosis and misdiagnosis in COPD.
Abstract
Overdiagnosis in the COPD literature generally refers to a false positive diagnosis (misdiagnosis). Misdiagnosis can be significantly reduced by performing spirometry in every patient with suspected COPD. http://ow.ly/zuAw30o7hiV
Background
Chronic obstructive pulmonary disease (COPD) is defined as “a preventable and treatable disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking” [1]. Despite COPD being a very common condition, there is no consensus on the diagnostic criteria for COPD [2]. COPD can be complex to diagnose, as a number of factors are relied upon to confirm the diagnosis, including a history of exposure to cigarette smoke or other noxious inhaled agents and the presence of chronic symptoms such as cough, wheeze or dyspnoea, as well as confirmed persistent airflow limitation on spirometry.
Lack of consensus regarding diagnostic criteria relates in particular to spirometry-based definitions. A study that assessed the impact of four different widely used spirometry-based definitions of airflow obstruction and one self-reported definition demonstrated that the population prevalence estimate of COPD altered by as much as 200% depending on which definition was used [2]. The four spirometry-based definitions included: 1) forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and FEV1 <80% predicted (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2) [3]; 2) FEV1/FVC below the lower limit of normal (LLN) [4]; 3) FEV1/FVC <88% predicted in males and <89% predicted in females [5]; 4) FEV1/FVC <0.7 (“fixed ratio”) (GOLD stage 1) [3].
In clinical practice, the GOLD definition of airflow obstruction based on post-bronchodilator FEV1/FVC of <0.7 is probably the most commonly used because it can be easily calculated, although the American Thoracic Society and the European Respiratory Society recommend the use of age- and sex-specific LLN for FEV1/FVC [6].
The need to use spirometry to diagnose COPD poses additional challenges beyond the lack of consensus about what constitutes relevant airflow obstruction. Spirometry requires that health professionals are trained in spirometry technique and patients need to be able to perform reproducible breathing manoeuvres. In many settings, especially in resource-constrained areas, a spirometer might not be readily available.
These challenges (lack of consensus on the definition of airflow obstruction, poorly performed spirometry and underuse of spirometry) can all have an impact on whether COPD is diagnosed in a patient or not and are associated with overdiagnosis, underdiagnosis and misdiagnosis of COPD.
The issues of overdiagnosis, underdiagnosis and misdiagnosis of COPD are not new. In recent years, there has been interest in overdiagnosis of different conditions, driven by an effort to address “too much medicine”, that is, healthcare interventions that have no net benefit for patients and may even result in harm [7]. In this context, overdiagnosis, especially related to cancer screening, has been defined as a true positive diagnosis of a condition that is not associated with any morbidity or mortality over a patient's lifetime (for example, diagnosis of an in situ breast cancer in an elderly woman, which will not cause any symptoms during her lifetime and will not be the cause of her death [7]). Even though the prevalence of overdiagnosis and misdiagnosis of COPD has been reported widely in the literature, it is unclear how the terms “overdiagnosis” and “misdiagnosis” in the context of COPD have been used.
A previous review has focused on estimating the prevalence of COPD and identifying causes of underdiagnosis and overdiagnosis in different health systems but did not focus on the terminology used [8]. Additionally, there has been a scoping review on misdiagnosis in COPD [9]. We performed a review of the literature to assess how the term “overdiagnosis” is used in the context of COPD.
Literature review
We conducted electronic searches of Medline from inception to October 2018 using the following search terms: “overdiagnosis” AND (COPD OR chronic obstructive pulmonary disease OR emphysema). We included original studies of any study design that reported on over- and/or misdiagnosis of COPD using these terms. We restricted our search to studies published in English. Relevant titles and abstracts were identified and eligible articles were included in this review. We also checked the reference lists of included studies.
From searches of Medline and PubMed, 42 records were identified, and a further 19 records were identified from reference list searches. From these we retrieved 50 articles for full-text review but 22 of these did not meet our selection criteria. 28 studies were included in our review (figure 1). The studies were published between 2003 and 2018 and were conducted in 13 countries.
Study flow diagram.
Definitions of overdiagnosis
In examining the 28 eligible studies, we identified several different types of “overdiagnosis” and “misdiagnosis”, which we have grouped in the categories described in the next sections and listed in table 1. Further details on each of the included studies can be found in table 2.
Types of overdiagnosis and misdiagnosis
Use of the terms “overdiagnosis” and “misdiagnosis” in the included studies
Physician COPD diagnosis, but with normal spirometry
15 studies reported overdiagnosis or misdiagnosis if the physician's diagnosis was discordant with the spirometry result, which showed either a normal or restrictive pattern [10–24]. A physician diagnosis with normal spirometry could have been a case in which the physician did not use spirometry to establish a diagnosis of COPD (and a normal spirometry was later found in the study) [10, 14–17, 21–23], or a case in which the physician “ignored” a normal spirometry result [12, 20, 24]. Most of these studies cited under-utilisation of spirometry as the primary cause of overdiagnosis and misdiagnosis in this context. Five studies used the term “overdiagnosis” to capture these discordant cases of physician diagnosis and spirometry readings [10–13, 17]. Eight studies considered these cases to be misdiagnosed [14, 15, 18–22, 24]. In two studies the terms “overdiagnosis” and misdiagnosis were used interchangeably to describe this concept [16, 23].
Fixed threshold for the definition of (post-bronchodilator) airflow obstruction
10 studies examined the effect of the fixed FEV1/FVC ratio (GOLD criteria) threshold for diagnosis of airflow obstruction in COPD [10, 14, 15, 17, 25–30]. The FEV1/FVC ratio is known to decline with age, and a fixed diagnostic threshold of FEV1/FVC <0.7 after bronchodilator administration does not take this into account. These studies compared the effect on COPD prevalence when using the fixed ratio compared to an age-adjusted definition of airflow obstruction or the LLN. The majority of these studies used the term “overdiagnosis” to describe a situation in which airflow obstruction was present using a definition of an FEV1/FVC ratio <0.7, but not when using the LLN [10, 15, 17, 25–28]. van Dijk et al. [30] and Steinacher et al. [29] used the terms “overdiagnosis” and “misdiagnosis” interchangeably when describing misclassification due to a diagnosis of airflow obstruction based on an FEV1/FVC ratio <0.7. Estimates of COPD overdiagnosis due to the fixed ratio ranged from 4.6% in a general population study that included people aged 40–80 years [27] to 42.7% in a study of people over the age of 80 years referred for spirometry by their general practitioners (GPs) [26].
Use of pre-bronchodilator spirometry only
One study explored the impact of using pre-bronchodilator spirometry on COPD prevalence [26]. To avoid misclassification with asthma (which is characterised by reversible airflow obstruction), a diagnosis of COPD must be based on airflow obstruction on spirometry performed after bronchodilator application. In the study of symptomatic adults referred for spirometry by their GPs, 25.3% of subjects with an obstructive pattern diagnosed by pre-bronchodilator spirometry were no longer classified as having COPD on post-bronchodilator spirometry. These cases were considered to be overdiagnosed.
Two studies reported misdiagnoses of physician-diagnosed COPD that later was found to be asthma after performing post-bronchodilator spirometry [19, 21].
Alternative diagnosis overlapping with COPD
Two studies performed spirometry in patients with known heart failure and found that, in this population, a substantial proportion of those diagnosed with COPD (12.3% in the first study [17] and 19.1% in the second study [29]) had been misdiagnosed using a definition of airflow obstruction based on FEV1/FVC <0.7 rather than FEV1/FVC <LLN. There is considerable overlap between the clinical features of heart failure and COPD.
The authors of one study attempted to detect airflow obstruction that was possibly masked by heart failure-related restriction (in 13 cases with an FEV1/FVC >LLN and an FVC <LLN) by experimentally substituting measured FVC by 80% of predicted FVC. This led to a decline of FEV1/FVC to <0.7 in eight cases and <LLN in seven cases [29].
One study reported that 19.5% of patients newly diagnosed with asthma had previously received an incorrect diagnosis of COPD and/or emphysema [31]. These cases were considered to be misdiagnosed cases and were attributed to the overlap in clinical features of asthma and COPD.
Follow-up spirometry appears normal
Llordés et al. [10] found that 16% of newly diagnosed cases of COPD had normal spirometry after 4 weeks of inhalation treatment with formoterol and budesonide. These diagnoses were named false positives or overdiagnosed cases.
Discussion
Findings of the review
In this review of 28 studies, the terms “overdiagnosis” and “misdiagnosis” of COPD were used interchangeably to describe the same concepts. These concepts included: 1) physician COPD diagnosis despite normal spirometry (no airflow obstruction at any point) in a situation where i) a normal spirometry result was documented before the study, ii) spirometry had not been performed before the study and the study showed normal spirometry results, or iii) it was unclear whether a spirometry had been performed before the study; 2) discordant results for COPD diagnosis based on different spirometry-based definitions for airflow obstruction (e.g. post-bronchodilator FEV1/FVC <0.7 or FEV1/FVC <LLN); 3) COPD diagnosis based on pre-bronchodilator spirometry results; 4) comorbidities that have clinical features overlapping with COPD and affect spirometry interpretation; 5) normalisation of abnormal (post-bronchodilator) spirometry at follow-up.
Comparison with other definitions of overdiagnosis and misdiagnosis
In some COPD studies, “overdiagnosis” has served as an umbrella term to include misdiagnosis. This is in contrast with the “narrow” definition of overdiagnosis, when an asymptomatic person is diagnosed with a (true positive) condition, but the diagnosis does not yield any change in mortality or morbidity for the individual [7]. However, this narrow definition poses a challenge when applied to COPD, as the diagnosis requires the presence of respiratory symptoms and screening of asymptomatic individuals is not recommended.
Brodersen et al. [32] proposed a definition of overdiagnosis that includes both overdetection and overdefinition, both leading to a diagnosis that causes more harm than benefit. “Overdetection” refers to an abnormal finding (e.g. a pulmonary nodule) that was never going to cause any harm, abnormalities that do not progress or progress so slowly that they will not cause any morbidity or mortality (e.g. non-aggressive prostate cancer), or that resolve spontaneously [33]. By extension, overdetection of COPD describes a diagnosis of COPD that, while correct, is not associated with any harm to the patient (e.g. mild emphysematous changes on computed tomography of the chest not requiring treatment and not significantly progressing). “Overdefinition” refers to lowering the threshold for a risk factor without clear evidence that this results in a net benefit (e.g. lowering the threshold for what constitutes a normal blood pressure) or by expanding disease definitions (e.g. pre-diabetes) [32].
The current GOLD definition for COPD (updated in 2017) requires the presence of persistent respiratory symptoms (in addition to meeting the spirometric definition of chronic airflow limitation) to make a COPD diagnosis [34]. Applying this definition of COPD is likely to reduce the rates of overdiagnosis in the population-based studies in this review that included asymptomatic patients (table 2). Spirometry-based definitions of airflow obstruction can result in overdefinition and thus overdiagnosis of COPD, e.g. when a FEV1/FVC ratio threshold of 0.7 is applied in elderly people. There is a potential risk of overdetection if asymptomatic people are screened for COPD, as the connection between mild airflow obstruction in asymptomatic people and subsequent development of symptomatic COPD is unclear. While the importance of early detection of COPD is often emphasised, this relates to detecting COPD early in symptomatic people. There is currently no evidence that supports spirometry screening of asymptomatic people for COPD [35]. A recent study demonstrated that treatment with bronchodilators in mild or moderate COPD can ameliorate the decline of lung function, but this study was conducted in symptomatic patients [36].
Recommended terminology for future research
Future meta-analyses that aim to explore the extent of COPD diagnostic errors should ideally use consistent terminology. For this purpose, it is important that the definitions of overdiagnosis and misdiagnosis used in the context of COPD are clarified. This review identified one main source of what we propose is COPD overdiagnosis: spirometry-based overdefinition of COPD based on the spirometric definition of airflow obstruction, e.g. when a FEV1/FVC ratio threshold of 0.7 is applied for airflow obstruction in elderly people. The onus lies on guideline contributors and authority bodies to provide more accurate definitions of airflow obstruction on spirometry.
We identified four sources of misdiagnosis of COPD: 1) physician COPD diagnosis despite normal spirometry; 2) COPD diagnosis based on pre-bronchodilator spirometry results (with normal result at follow-up); 3) comorbidities (e.g. heart failure, asthma) that affect spirometry and have clinical features which overlap with COPD; and 4) normalisation of abnormal post-bronchodilator spirometry at follow-up (e.g. in asthma).
Figure 2 demonstrates the variety of factors that need to be considered when making a diagnosis of COPD.
Components of a COPD diagnosis.
Study limitations
A limitation of some of the studies in this review is that the prevalence of COPD (and COPD overdiagnosis) was only defined based on a spirometry definition of airflow obstruction (comparable to defining the prevalence of arterial hypertension based on blood pressure measurements in a population), not taking into account that in clinical practice the diagnosis of COPD is a complex issue and the clinical history (symptoms consistent with COPD, exposure to inhaled noxious agent) and ruling out potential differential diagnoses are also essential in making a diagnosis.
While potential adverse events of overtreatment (which can be the result of overdiagnosis) for COPD may not be as severe as for overtreatment of cancer, it is important to keep in mind that all medications have the potential to cause harm and are associated with work that patients need to do to enact treatment recommendations [37].
While this review has focused on overdiagnosis and misdiagnosis, underdiagnosis of COPD is even more common and both overdiagnosis and underdiagnosis can often be explained by underuse or inappropriate use of spirometry [8].
In summary, overdiagnosis of COPD has been used in the reviewed literature to describe both a false positive diagnosis of COPD and overdefinition based on diagnostic criteria. With the introduction of the new GOLD definition of COPD requiring the presence of symptoms, overdefinition and thus overdiagnosis of COPD in population-based studies will probably be reduced. Misdiagnosis of COPD (in addition to underdiagnosis) remains a major diagnostic challenge. To reduce misdiagnosis, clinicians should perform (technically correct) spirometry in all symptomatic patients with clinically suspected COPD.
Footnotes
Author contributions E.T. Thomas was involved with devising the review methods, conducting electronic searches, screening of abstracts, data extraction and interpretation, and co-drafting of the review. P. Glasziou was involved with devising the review methods, data interpretation and co-drafting the review. C.C. Dobler conceived the original idea, and was involved with devising the review methods, data interpretation and co-drafting the review.
Conflict of interest: E.T. Thomas has nothing to disclose.
Conflict of interest: P. Glasziou reports a 5-year Program Grant (2017–2021) on overdiagnosis from the Australian National Health and Medical Research Council, outside the submitted work.
Conflict of interest: C.C. Dobler has nothing to disclose.
Support statement P. Glasziou and C.C. Dobler have received funding from the Australian National Health and Medical Research Council (P. Glasziou: Australia Fellowship No. 527500 and Program Grant No. 633003; C.C. Dobler: Fellowship No. APP1123733). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
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References
