Factors associated with undiagnosed COPD in patients hospitalised for severe COPD exacerbation

Abstract

Background

Studies suggest that up to 70% of chronic obstructive pulmonary disease (COPD) cases globally are undiagnosed worldwide. Some of these undiagnosed patients may present with severe exacerbation and factors associated with underdiagnosis in this population are unknown. We investigated the key factors associated with underdiagnosis in two cohorts of patients hospitalised for severe COPD exacerbation at different time points.

Methods

This retrospective, multicentre study analysed data from patients hospitalised for COPD exacerbation at two independent centres during two distinct time periods: between 1 January 2017 and 31 December 2018 in the Aquitaine region and between 1 January and 31 December 2022 in Paris. Undiagnosed COPD was defined as the absence of pulmonary function testing before the index exacerbation. Multivariate logistic regression was used to evaluate associations between underdiagnosis and patient characteristics.

Results

Among the 424 patients, 93 (21.9%) were undiagnosed before hospitalisation, with a stable rate over time (22% in 2017–2018 and 21% in 2022). Multivariate analysis revealed that underdiagnosis was related to higher forced expiratory volume in one second (FEV₁; adjusted OR (aOR)=1.02, p=0.043) and female sex (aOR=1.91, p=0.015). Patients with undiagnosed COPD had significantly lower rehospitalisation and mortality rates. After the initial severe exacerbation, higher mortality was associated with a higher Charlson Comorbidity Index (HR=1.24, p=0.007) and older age (HR=1.05, p=0.008).

Conclusion

This retrospective, multicentre study demonstrated that about 20% of patients admitted with severe exacerbation were undiagnosed for COPD. Higher FEV₁ and female sex were associated with underdiagnosis, emphasising the need for special attention to this population. These findings highlight the need to improve training and access to spirometry and develop new diagnostic tools that facilitate earlier detection and management of COPD.

Correspondence to Dr Marina Guecamburu; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Undiagnosed chronic obstructive pulmonary disease (COPD) patients may present with severe exacerbation, but factors associated with underdiagnosis in this population are unknown.

WHAT THIS STUDY ADDS

• About 20% of patients admitted with severe exacerbation of COPD were undiagnosed before hospitalisation, with a stable rate over time. Factors associated with undiagnosis were a higher forced expiratory volume in one second and female sex.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• There is a real need to improve access to spirometry and to develop new diagnostic tools to facilitate earlier detection in primary care.

Background

Chronic obstructive pulmonary disease (COPD), a chronic disease with high morbidity and mortality rates, is projected to become the fourth leading cause of death worldwide by 2030.¹ Its course is marked by acute events known as exacerbations, which potentially lead to hospitalisation.² These are major life events with long-term negative consequences, including declines in lung function^{3 4} and quality of life.⁵ Diagnosis is based on a combination of chronic respiratory symptoms and pulmonary function tests (PFTs), showing airway obstruction that is not entirely reversible. However, a lack of screening recommendations and limited access to spirometry are important barriers to diagnosis. The results of previous studies have suggested that up to 70% of COPD cases worldwide remain undiagnosed.^{6 7} The recent COPDGene study by Tran et al⁸ revealed that 1064 (21%) patients in the cohort exhibited undiagnosed airflow obstruction before enrolment. Age, number of pack-years, current smoking and a history of acute bronchitis were associated with airflow obstruction, whereas body mass index, female sex and black race showed inverse associations. COPD underdiagnosis can significantly impact morbidity and mortality. Patients with undiagnosed COPD have increased risks of exacerbation, pneumonia and mortality, mainly due to associated respiratory symptoms.⁹ Therefore, confirming the diagnosis with spirometry is crucial: first, to avoid misdiagnosis; second, because this medication has shown no benefit for symptomatic individuals with tobacco exposure who have preserved lung function.¹⁰ These findings suggest an urgent need to identify factors associated with COPD underdiagnosis; such factors can facilitate case finding, early diagnosis and management.

Therefore, the present study aimed to identify the main factors associated with underdiagnosis at two time points in two independent cohorts of patients hospitalised for severe COPD exacerbation in France.

Methods

Data sources

This retrospective, multicentre study included two independent cohorts of patients hospitalised for a severe COPD exacerbation in France, at two time points. The first cohort included patients in three pulmonary departments in Southwest France (Bordeaux, Bayonne and Libourne) between 1 January 2017 and 31 December 2018, while the second cohort included patients admitted to the respiratory intensive care unit (ICU) of the European Hospital Georges Pompidou in Paris between 1 January and 31 December 2022. Patients were identified using ‘Programme de Médicalisation des Systèmes d’Information’ (PMSI) codes, which correspond to the French national hospital discharge database and include hospital diagnoses and medical procedures performed during each stay in French public hospitals (online supplemental table S1). Data were individually extracted from medical records. Annual income, according to city of residence or address, was obtained from the public website ‘Geoportail’ (https://www.geoportail.gouv.fr/).

Study population

The study included patients aged≥40 years who were hospitalised for at least one night due to COPD exacerbation. We used PMSI codes, based on the International Classification of Diseases-10, to select patients with a principal diagnosis of COPD or patients with a principal diagnosis of acute respiratory failure, respiratory infection, influenza, acute heart failure or pneumothorax combined with a secondary associated diagnosis of COPD (online supplemental table S1).¹¹ Exacerbation criteria were defined as acute worsening of respiratory symptoms requiring additional therapy and hospitalisation.² Patients were excluded if they did not have a forced expiratory volume in one second/forced ventilatory capacity ratio (FEV₁/FVC) of <0.70 on PFTs, either before admission or during the pulmonologist follow-up visit for an initial COPD diagnosis; if they had a diagnosis other than COPD (eg, COVID-19, bronchiectasis or asthma); or if they did not meet the COPD exacerbation criteria.

Outcomes

Undiagnosed COPD was defined as the presence of COPD without prior identification and without pulmonary function testing before the index exacerbation. COPD was confirmed only during the first follow-up consultation. Some of them could already receive inhaled treatment, suggesting underlying respiratory symptoms but with no previous PFT testing. Previously diagnosed COPD was defined as a patient with an FEV₁/FVC<0.70 prior to hospitalisation. Factors associated with underdiagnosis were analysed. Frequent exacerbators were defined as patients who had more than two moderate exacerbations or one severe exacerbation in the past 12 months.

Patient and public involvement

Patients and public were not involved in the study design and conduction

Statistical analyses

Categorical variables were compared using the χ² test or Fisher’s exact test. Continuous variables are presented as means±SD and were compared using Student’s t-test. Factors associated with undiagnosed COPD were estimated using a multivariate logistic regression model and quantified as adjusted ORs (aORs) with 95% CIs. Variable included in the multivariate analysis were age, sex, Charlson Comorbidity Index, FEV₁ and smoking. Potential confounding factors were identified from the literature.¹² The threshold for statistical significance was set to p<0.05. Mortality differences between groups were analysed using the log-rank test, and a Cox model was used to evaluate potential associated factors. We used the programming language R (V.4.2.0) with the ‘stats’ package (V.4.2.0) for multivariate analysis. All other analyses were performed with Microsoft Excel and GraphPad Prism software.

Results

Patient characteristics

The selected PMSI codes were used to identify 1840 patients (1180 in Bordeaux, Libourne and Bayonne between 1 January 2017 and 31 December 2018 and 660 at the European Hospital Georges Pompidou, Paris, between 1 January and 31 December 2022). After analyses of medical records, 1416 patients were excluded, primarily due to a diagnosis other than COPD exacerbation (figure 1). Thus, 424 patients hospitalised for severe COPD exacerbation were finally included; these patients were 39% women, had a mean age of 68.7±10.2 years and displayed a Charlson Comorbidity Index of 1.5±1.9. 31 patients (7%) were categorised as frequent exacerbators. ICU admission at the time of hospitalisation was required in 105 patients (25%). Additionally, 67 patients (15%) did not have any inhaled treatment, and 198 patients (47%) were active smokers at the time of hospitalisation (table 1).

Figure 1. Flow chart. COPD, chronic obstructive pulmonary disease; PMSI, Programme de Médicalisation des Systèmes d’Information.

Table 1

Comparison of patients with or without a COPD diagnosis before hospitalisation for severe acute exacerbation

	Total population	Undiagnosed COPD	Previously diagnosed COPD	P value
	n=424	n=93 (22%)	n=331 (78%)
Demographic characteristics
Female	166 (39)	50 (54)	116 (35)	0.001
Age (years)	68.7±10.2	66.7±9.8	69.2±10.3	0.03
Current smokers	198 (47)	62 (67)	136 (41)	<0.0001
Smoking history (pack-years)	48.3±23.8	47.2±22.1	48.6±24.3	0.56
Profession*
Current activity	33 (8)	10 (11)	23 (7)	0.27
Disability	60 (15)	13 (14)	47 (14)	1.00
Retired or unemployed	290 (68)	60 (65)	231 (70)	0.31
Annual income (€)†	24 717.9±5898.9	25 222.8±7219.3	24 577.5±5405.1	0.26
Comorbidities
Charlson Comorbidity Index	1.5±1.9	1.3±1.8	1.6±1.9	0.04
Cardiovascular comorbidity‡	0.6±0.8	0.5±0.7	0.6±0.8	0.27
Exacerbation features
Inaugural severe exacerbation	258 (61)	72 (78)	186 (56)	0.0002
Frequent exacerbators§	31 (7)	2 (2)	29 (9)	0.04
ICU admission	105 (25)	29 (31)	76 (23)	0.13
Respiratory function parameters
FEV1/FVC	50.7±11.8	53.9±10.8	49.8±12.0	0.006
FEV1 (%)	44.8±16.8	48.3±16.0	43.8±16.8	0.02
TLC (%)	110±26	112±25	111±26	0.98
COPD treatment prior to hospitalisation
No inhaled treatment	67 (15)	37 (40)	30 (9)	<0.0001
Monotherapy	29 (7)	10 (11)	19 (6)	0.07
LABA+LAMA	123 (29)	23 (25)	100 (30)
LABA+ICS	59 (14)	9 (10)	50 (15)
LABA+LAMA+ICS	141 (33)	13 (14)	128 (39)
Oxygen therapy	129 (30)	8 (9)	121 (37)	<0.0001
NIV	66 (16)	4 (4)	62 (19)	0.0003
Influenza vaccination¶	115 (27)	11 (12)	104 (32)	0.0001
Pneumococcal vaccination**	99 (23)	4 (4)	95 (29)	<0.0001
PR in previous 12 months††	106 (25)	5 (5)	101 (31)	<0.0001
Rehospitalisation at 12 months	103 (24)	10 (11)	93 (28)	0.0003
Death within 12 months after discharge	29 (7)	3 (3)	26 (8)	0.16

Data are presented as means±SD or absolute values (percentages).

*Declared profession, 40 (9%) missing values.

†Annual income in euros, according to city of residence or address and obtained from the public website ‘Geoportail’ (https://www.geoportail.gouv.fr/).

‡Cardiovascular comorbidities included myocardial infarction, heart failure, peripheral vascular disease, stroke with or without sequelae or transient ischaemic attack.

§Frequent exacerbators: ≥2 moderate and/or ≥1severe exacerbations in the past 12 months.

¶165 (39%) missing values.

**149 (35%) missing values.

††79 (18%) missing values.

COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; ICS, inhaled corticosteroids; ICU, intensive care unit; LABA, long-acting β2-agonists; LAMA, long-acting muscarinic antagonists; NIV, non-invasive ventilation; PR, pulmonary rehabilitation; TLC, total lung capacity.

Factors associated with previously undiagnosed COPD

Among the 424 patients admitted for severe COPD exacerbation, 93 (21.9%) did not have a COPD diagnosis, assessed with spirometry, at the time of hospitalisation. The underdiagnosis rate remained stable over time, in both centres (22% in 2017–2018 and 21% in 2022) (online supplemental table S2).

Patients with undiagnosed COPD were more likely to be women (54% vs 35%, p=0.001), younger (66.7 years vs 69.2 years, p=0.03) and active smokers (67% vs 41%, p<0.0001) (table 1). They had fewer comorbidities, indicated by a lower Charlson Comorbidity Index (1.3±1.8 vs 1.6±1.9, p=0.04) and a higher mean FEV₁ (48.3±16.0%). Undiagnosed patients also had significantly fewer inhaled treatments at the time of hospitalisation (p<0.0001). Regarding socioeconomic factors, there was no significant difference in terms of current professional activity or annual income between the groups. However, 68% of the patients were retired or unemployed (table 1).

According to multivariate analysis (figure 2), patients with undiagnosed COPD had a higher FEV₁ (aOR=1.02 (1.00–1.03), p=0.04) and were more likely to be women (aOR=1.91 (1.13–3.22), p=0.01). There were no baseline differences in these characteristics between the two cohorts (online supplemental table S2).

Figure 2. Forest plot of multivariate logistic regression analysis of association between patient characteristics and undiagnosed chronic obstructive pulmonary disease. aOR, adjusted OR; FEV 1 , forced expiratory volume in one second.

The rehospitalisation rate was lower in patients with undiagnosed COPD (p=0.0003) (table 1). Mortality was significantly lower among patients with undiagnosed COPD in the whole cohort (p=0.0029, figure 3A) and among patients with a first severe COPD exacerbation (p=0.017, figure 3B). Among patients with a first severe COPD exacerbation, factors associated with mortality included a higher Charlson Comorbidity Index (HR=1.24, 95% CI: 1.07 to 1.43, p=0.003) and older age (HR=1.05, 95% CI: 1.01 to 1.08, p=0.008) (figure 4).

Figure 3. Survival according to delay in the whole cohort (A) and after the first severe chronic obstructive pulmonary disease (COPD) exacerbation (B). aOR, adjusted OR.

Figure 4. Forrest plot of cox model of factors associated with mortality in the whole cohort and among patients with first severe COPD exacerbation. COPD, chronic obstructive pulmonary disease; FEV 1 , forced expiratory volume in one second.

Discussion

This study focused on patients with undiagnosed COPD within two independent cohorts (Southwest France and Paris) at two different time points (2017–2018 and 2021–2022). Among 424 patients admitted for severe COPD exacerbation, 93 (21.9%) did not have a previous COPD diagnosis. This rate was stable over time and higher than in previous studies.^{7 9} In a lung cancer screening cohort (3920 patients),⁷ 17% of the patients had undiagnosed airflow obstruction associated with respiratory symptoms. In a Danish cohort,⁹ among 32 518 screened individuals, 2903 (8.9%) had undiagnosed airflow limitation with a smoking history of more than 10 pack-years and no asthma. Among these patients, 2052 were symptomatic and 6.3% met all diagnostic criteria for COPD. Finally, in a French population-based cohort study conducted in 2013–2014,¹² involving adults aged 18–69 years, 64.4% of patients with airflow limitation had no prior diagnosis of obstructive lung disease. The likelihood of being undiagnosed was higher among individuals with significant tobacco exposure (≥10 pack-years) and those with preserved lung function. Unlike these three previous studies, we included a more specific patient population, identified by exacerbation history, explaining our higher but stable rate of underdiagnosis over time.

Patient-related factors associated with underdiagnosis

In our study, patients with undiagnosed COPD were more likely to be women. Although COPD prevalence among women has equalled the prevalence among men since 2008,¹³ a study in the UK demonstrated that general practitioners (GPs) are less likely to suspect COPD in women than in men, leading to more missed opportunities for COPD diagnosis in primary care.¹⁴ The clinical presentation may differ between men and women, with less cough, sputum, smoking and different occupational and environmental exposures in women, but more dyspnoea, anxiety and depression.¹⁵ This is particularly important because women with COPD report worse quality of life, experience a more rapid decline in lung function and have more frequent exacerbations and hospitalisations.^{16 17} Stolz et al¹⁸ reported that the risk of a first moderate or severe exacerbation was 17% greater in women than in men (HR=1.17; 95% CI: 1.12 to 1.23). Our study highlights the importance of raising awareness among GPs about COPD case finding in women. Furthermore, we found that patients with undiagnosed COPD were younger, had fewer comorbidities, displayed better lung function and were more often active smokers, consistent with the results in previous studies.^{7 19} Additionally, these patients are less likely to be symptomatic.⁷ However, we were unable to explore these results further because symptom scores were unavailable. Finally, access to accurate diagnosis can substantially vary according to socioeconomic status or geographical location.²⁰ In our study, socioeconomic status was not significantly associated with underdiagnosis, probably because we only considered annual income based on residence; we did not have access to household composition or education level.

Impact of exacerbations on lung function

According to blood gas analyses and ICU admission rates, undiagnosed patients tended to have less severe exacerbations than patients who were previously diagnosed. Additionally, previously diagnosed patients had significantly higher rates of rehospitalisation at 12 months and mortality, possibly related to disease severity. COPD exacerbations are considered major events leading to functional decline and changes in quality of life, which may persist for several weeks after the acute event.²¹ Halpin et al⁴ demonstrated that the mean annual FEV₁ decline increased after a single moderate-to-severe exacerbation compared with the FEV₁ decline prior to the exacerbation (76.5 mL/year vs 39.1 mL/year, p=0.003). This difference appears to be related to exacerbation severity.⁵ COPD represents a major risk factor for healthcare-associated infections in the ICU and prolonged mechanical ventilation may contribute to the worsening of comorbidities, such as muscle loss.²² Furthermore, de Nigris et al²³ demonstrated that increases in healthcare resource utilisation and costs associated with COPD exacerbations are related to exacerbation number and severity; this relationship persists for up to 36 months. Therefore, exacerbations should be avoided to maintain a sustainable healthcare system.

Potential solutions for improving diagnosis and spirometry access

Currently, the National Screening Committee and the US Preventive Services Task Force do not recommend COPD case finding in asymptomatic or mildly symptomatic adults due to the lack of specificity of questionnaires assessing symptoms and the limited value of spirometry alone.²⁴ A similar position has been adopted by the UK National Screening Committee.²⁵ The limited availability of spirometry in primary care,²⁶ along with the reliance on isolated obstruction for diagnosis, highlights the need to develop new tools for the early identification of patients with a high risk of undiagnosed COPD.

Martinez et al²⁷ investigated case finding in primary care for 4325 patients using both the ‘COPD Assessment in Primary Care To identify Undiagnosed Respiratory disease and Exacerbation Risk’ Questionnaire and peak expiratory flow measurements. The questionnaire consists of five questions regarding: (1) exposure to pollution and smoking, (2) variations in respiratory symptoms according to season, weather or air quality, (3) activity-related breathing difficulties, (4) presence of asthenia compared with people of the same age and (5) absence from work, school or other activities due to colds, bronchitis or pneumopathy. Among the 4325 included patients, 2.5% had confirmed COPD. Although the sensitivity of this case finding tool was relatively low (48.2%), it had good specificity (88.6%). This tool also had good sensitivity in identifying patients with COPD who require treatment due to increased risk of exacerbations or hospitalisation.²⁸ In France, Chapron et al²⁹ studied the effect of five Global Initiative for Chronic Obstructive Lung Disease (GOLD) questions (age>40 years, three questions regarding symptoms and one question regarding exposure) assessed by GPs and/or referral to a COPD coordinator compared with the control group for diagnosis of COPD among 3162 patients aged≥40 years in primary care. All new COPD cases (n=24, 0.8%) were diagnosed in the intervention groups (GOLD questions or COPD coordinator), representing 6.8% of patients who had undergone spirometry. A meta-analysis of 39 studies in adults aged 35 years and over in primary care showed that, despite study heterogeneity, incorporating an initial screening test before spirometry generally improved diagnostic accuracy.³⁰ The percentage of COPD diagnoses among those referred for spirometry ranged from 14.3% to 42.1% with screening questionnaires, compared with 4.1% to 40.2% without.

Identification of the right population for COPD case finding in primary care is an important challenge. In the aforementioned French study, the authors focused on patients aged≥40 years, representing a large number of patients. In a cohort of 2273 patients followed up over 6 years, Divo et al³¹ found that the strongest independent predictors of chronic airflow limitation were FEV₁/FVC<0.75, smoking history of >30 pack-years, body mass index<25 kg/m² and symptoms of chronic bronchitis. GP training in the use and interpretation of spirometry could be an important mechanism for reducing underdiagnosis. In France, although the overall number of French GPs decreased by 6534 (9.8%) between 2010 and 2018, the number of non-expert GPs performing spirometry increased from 681 (1.02% of all GPs) in 2010 to 1683 (2.80%) in 2018, representing 114.4 new GPs each year.²⁶ Therefore, the use of tools that consider both clinical factors and PFTs could reduce the underdiagnosis rate in a selected population of current smokers.

Limitations

A main strength of our study was the inclusion of two time points (ie, 2017–2018 and 2022), demonstrating a stable underdiagnosis rate over time. However, its retrospective design and the use of exhaustive PMSI codes made patient selection reliant on the accuracy of coding performed by practitioners. This reliance led to the exclusion of more than half of the population and resulted in some missing data. Detailed individual analysis of each medical record was performed to mitigate this limitation. Additionally, 60% of the patients considered undiagnosed had received inhaled treatment, highlighting the challenges in accessing spirometry or pulmonologists for confirming a COPD diagnosis in the presence of respiratory symptoms. Finally, despite the exclusion of 10% of the patients in the second cohort, primarily because of SARS-CoV-2 infections, the underdiagnosis rate remained comparable between the two cohorts.

Conclusions

COPD underdiagnosis is a major public health problem. The present study demonstrated that the underdiagnosis rate was dramatically high (21.9%) in two independent cohorts, but it remained stable over time among patients hospitalised for COPD exacerbation, particularly among women. This study highlights the need to raise awareness among GPs about COPD screening in women and develop new tools for early diagnosis.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

This study involves human participants but According to French Law, this anonymous retrospective observational database study does not require approval by an ethics committee or informed signed consent from the patients. The study was designed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and registered with the following number CHUBX2021RE0253.

Footnote

X @MGuecamburu

Contributors MG: Study concept, methodology, validation, formal analysis, investigation, writing—original draft. EK: Study concept, methodology, validation, formal analysis, investigation, writing—manuscript preparation and drafting. GV: Study concept, methodology, data analysis and interpretation, writing—manuscript preparation and drafting. CN-E, JM and LP: Study concept, validation, writing—manuscript preparation and drafting. LG: Study concept, methodology, validation, writing—manuscript preparation and drafting. TS and MZ: Study concept, methodology, validation, formal analysis, writing—manuscript preparation and drafting. All authors have read and approved the manuscript. MZ is the guarantor of this work.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests MG, EK, GV and LP have no conflicts of interest to disclose. CN-E reports grants and personal fees from GSK, Sanofi, AstraZeneca, Chiesi, ALK and Menarini outside the submitted work. JM has no conflicts of interest to declare. LG has no conflict of interest to declare related to the present work. He received grants from AADAIRC. He received speaker or advisory board fees from GSK, Asten, Air Liquide Medical System, Sanofi Genzyme, SOS Oxygène, AstraZeneca, ASV, Boehringer, VIVISOL and ResMed and support for attending the meeting from SOS Oxygène, Alize Santé and Asten. TS reports personal fees from Menarini, Sanofi, Chiesi, AstraZeneca, GSK outside the submitted work. MZ reports grants and personal fees from Menarini, personal fees from Sanofi, personal fees from Chiesi, personal fees from AstraZeneca, personal fees from CSL Behring and personal fees from GSK outside the submitted work, grants from AVAD, grants from FRM.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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