Real-World Clinical Data Identifies Gender-related Profiles in Chronic Obstructive Pulmonary Disease

Abstract

This study aims to compare diagnostic and clinical outcomes of Chronic Obstructive Pulmonary Disease (COPD) from the gender perspective using retrospective health care data and patient reported outcomes in a real-world setting. An electronic database was constructed from complete medical records of 844 COPD patients who were recruited in Helsinki and Turku University Central Hospitals during the years 2005—07. The patients were identified from the hospital discharge registries by ICD10 code J44.8 in the age group of 18–75 years of age. The medical history was obtained from all healthcare providers who had treated these patients during the previous 5-10 years; the study intends to continue their follow-up annually for the next 10 years. Thirty-six percent (N = 266) of the participants were women. The COPD diagnosis had been made at the same age for both genders. Women, however, reported significantly less pack-years than men. Compared to the men, the women displayed less advanced airway obstruction, but more severe gas transfer impairment. Parenchymal damage when evaluated by diffusion capacity correlated significantly stronger with FEV₁ (% of predicted) in women than men. The BMI index of the women was lower than that of the men. Cardiovascular diseases, diabetes and alcoholism were significantly more common in men, but women suffered more psychiatric conditions, especially depression. This cohort showed several significant gender dependent differences in the clinical presentation that need to taken under consideration in the assessment of COPD progression and the disease management.

Keywords:

• Gender
• COPD
• GOLD

INTRODUCTION

There is growing evidence that women are at greater risk than men of suffering smoking-induced lung function impairment and mortality ([1]). In the United States, the number of women dying of COPD has already surpassed the numbers of men ([2]). The most important reason for increased numbers of female COPD sufferers is related to the lifestyle/increased smoking of women worldwide. There are, however, studies indicating that gender plays an essential role in clinical outcome of the disease (3–7). It is clear that co-morbidities play an important role in COPD, and these also may vary between the genders (reviewed by Han et al. ([1]).

Despite multiple investigations it is still difficult to draw final conclusions on the impact of gender in COPD. There is evidence that the diagnosis of COPD in women can be delayed ([8]). Women have been underrepresented in many clinical trials, which in turn may result in inadequate diagnoses and suboptimal management. Large multicentered studies often concentrate on a particular patient group that does not represent COPD patients at large. Most studies use the GOLD criteria (www.GOLD.com)([9]) for COPD diagnosis and ignore parenchymal changes. The GOLD classification has been widely criticized since it uses a fixed cut off point (FEV₁/FVC < 70%) for COPD diagnosis. As far as to variability in obstruction/emphysema is concerned, the NETT (National Emphysema Treatment Trial ([10])) study did evaluate severe and very severe cases of COPD and reported gender related changes in lung parenchyma by HRCT and histological evaluation ([4]). The use of registry based cohorts in the evaluation of gender related COPD features suffers from many drawbacks such as the variability and possible changes in the provision of health care in the community.

Moreover, surveys in different parts of the world vary that are related, not only to different health care organizations, but also to the significant cultural differences, prevalence of smoking, genetic background, and the possibility for patients to receive treatment of COPD ([1]). The role of gender in the assessment of COPD is still unclear, and even less is known about potential gender related differences in subphenotypes, co-morbidities, and disease progression.

Finland has strong traditions both in epidemiology and clinical research. Additionally, there are several other elements that can promote hospital/health care based longitudinal investigations in Finland. National guidelines for diagnostics and treatment are carefully followed by physicians, since the patients are eligible for significant reimbursements by the Finnish Institute of Social Insurance if certain criteria are met and documented. In addition to the uniformity in clinical practice, public health care is of a high standard and available to all. The guidelines for asthma and COPD are widely recognized and implemented in health care throughout the whole country ([11],[12]). The Finnish population is also genetically and culturally very homogeneous population with a high standard of living.

We have collected an electronic database that includes complete medical records of 844 COPD patients whose COPD diagnosis has been evaluated by an expert physician. All documents from each individual both in the hospital and outpatient clinics have undergone detailed scrutiny to analyse clinical differences between genders at the time of diagnosis of COPD.

MATERIALS AND METHODS

Subjects

Hospital Discharge Registries were used to identify all patients with COPD who had visited the Pulmonary Clinics of the Helsinki (HUCH) and Turku (TUCH) University Hospitals during the years 1995–2006. The databases were screened by ICD10 code J44.8 and contained all patients between 18 to75 years of age. All identified patients were invited to the study without further selection (Figure 1). The recruitment was done through a two phase mailing campaign, the first step including the mailing of 3075 letters. The letter signed by the head physician of their home clinic was short and explained the study approach at a general level. Then, 1672 patients responded by giving their contact information to the research consortium. The subsequent letter included detailed information of the study including the consent form. In total, 844 patients contacted the researchers by phone and agreed on a visit to the clinical research center in Helsinki or Turku. No further reminders were mailed.

Figure 1 Recruitment process of the COPD patients in the two main university hospital districts of southern Finland years 2005–2007.

The research visits occurred during the years 2005–2007. Due to complexity of the study approach, trained research nurses carefully explained the research scope and the purpose of the study. All the participants gave their informed consent to allow the research consortium to collect, merge, and analyze their comprehensive medical history from all the healthcare providers who had treated them during the past 5–10 years and agreed to continue their follow-up on an annual basis for the next 10 years.

The interview concentrated an obtaining a full history of the disease including all health care providers, both community health centers and private physicians, who had been involved in the treatment of the patients during the previous 5 years. The search at the specialist level included all consultations in Pulmonary Medicine, Internal Medicine, and Laryngo-rhinology. When available, older data (over 5 years) was collected from the two University Hospitals.

Further, the consent permitted inclusion of all available information from some other highly detailed national health care registries. In addition to annual reports and the new health care contacts, the participants will report their present smoking status, possible sick leaves, retirements, rehabilitation, and health related quality of life, (13, 14, Mazur et al. unpublished). Annual deaths will be followed from the national population registry. During the research visit all the participants also donated a 7 ml citrate blood sample for DNA extraction. The participants are free to withdraw from the study at any time.

Data processing

All the hospitals, health care centers, and other outpatient clinics that had treated the patients were contacted to archive a complete, unbroken medical history for each participant. The patients' social security number was used to combine the data from different sources. Source data with personal identifiers was managed and stored in the Clinical Research Centers administered by the Helsinki and Turku University Hospitals. Data that existed only on paper was scanned. The scanned and decoded medical records include the original notes of the physicians and copies of various diagnostic tests such as results of spirometry, diffusion capacity, and ECG traces. The reference values for FEV₁, FVC, PEF, and DLCOcVA used in Finnish clinical practice are validated in large Finnish population samples consisted of both genders and a wide range of age groups ([15]). The study approach was approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District and the permission to conduct this research was granted by the Helsinki and Turku University Hospitals.

Statistical analysis

The SPSS computer package was used to compute differences in demographic and clinical variables. Continuous variables were compared between the genders using the non-parametric Mann–Whitney U-test and categorical variables were compared using the Chi²-test. We used linear regression (dependent DLCOcVA, explanatory variables gender, height, age, FEV₁ and gender* FEV₁ interaction term) to study whether the strength of correlation between FEV₁ and DLCOcVA differed significantly between the genders.

This analysis is based solely on retrospective clinical data. After exclusion of the patient groups with scanty documentation, the proportion of missing data for each variable decreased to the level of < 11% except for DLCOcVA. Results of diffusion capacity measurements were available for 56% of patients (N = 413, 52% of women and 58% of men). Regarding the clinical variables shown in Table 1, no significant differences between tested and non-tested individuals could be observed. Thus, the data was considered in the analyses as ‘missing at random’.

Table 1 Basic clinical characteristics compared between men and women participating the study

Characteristic feature	Men N = 473	Women N = 266	Significance p-value
Age, mean (yrs)	59 (± SD 7.3)	58 (± SD 7.0)	ns.
Duration of the disease, mean (yrs)	5.6 (± SD 4.4)	5.6 (± SD 3.6)	ns.
Pack-years, mean	55 (± SD 20)	45 (± SD 18)	< 0.0001^1
Baseline (% predicted, mean)
• FEV1	56.6 (±SD 18.7)	61.4 (±SD 18.8)	0.001^1
• FVC	72.0 (±SD 18.4)	76.2 (±SD 17.2)	0.004^1
• FEV1/FVC	0.63 (±SD 0.14)	0.65 (±SD 0.15)	ns.
• PEF	63.6 (± SD 20.7)	67.8 (±SD 22.1)	0.03^1
After bronchodilatation (% of predicted)
• FEV1	59.9 (± SD 17.8)	65,7 (±SD 17.4)	< 0.0001^1
• FVC	75.8 (±SD 17.2)	80.4 (±SD 16.4)	0.005^1
• FEV1/FVC ratio	0.64 (±SD 0.13)	0.66 (±SD 0.14)	0.005^1
• PEF	67.5 (±SD 20.2)	72.2 (±SD 21.5)	0.002^1
Proportion (%) of patients with
• FEV1>80 %	14.3	20.9
• 50%≤FEV1 < 80%	55.3	58.2
• 30%≤FEV1 < 50%	23.3	17.3	0.002^2
• FEV1<30%	7.0	3.6
GOLD criteria
• Stage 0: FEV1>80%	10.2	18.5	0.001^2
• Stage 1: FEV1/FVC < 70%, FEV1 ≥ 80%	4.1	2.4
• Stage 2: FEV1/FVC < 70%, 50%≤FEV1 < 80%	34.2	32.5
• Stage 3: FEV1/FVC < 70%, 30%≤FEV1 < 50%	21.4	16.5
• Stage 4: FEV1/FVC < 70%, FEV1 < 30%	6.3	3.6
• undetermined: FEV1/FVC ≥ 70%, FEV1 < 80%	23.1	26.5
DLCOcVA (% of predicted)	78.0 (±SD 21.7)	72.4 (±SD 22.1)	0.03^1
General health related QoL score (range 0-1)	0.79 (±SD 0.11)	0.79 (±SD 0.11)	ns.
Airway specific QoL score (range 20-0)	7.9 (±SD 5.0)	8.8 (±SD 5.1)	0.03^1
BMI index, mean	27.1 (±SD 4.7)	25.6 (±SD 6.1)	< 0.0001^1
Proportion of patients with concomitant
• Coronary disease	26.6	12.4	< 0.000^2
• Cerebrovascular disease	8.9	5.3	0.05^2
• Diabetes	17.5	10.5	0.006^2
• Claudication	5.7	2.3	0.02^2
• Alcoholism	18.2	9.0	< 0.000^2
• Psychiatric disorders	8.7	13.2	0.06^2
• Hypertension	41.2	39.5	ks

¹Mann-Whitney U-test ²Chi-square test.

RESULTS

Patient recruitment and selection

A total of 844 patients attended the interview, donated the blood sample, and signed the informed consent. The final recruitment rate was 27%. No differences between age or gender distributions could be found between the responders and non-responders. The cohort has been so far followed 1-3 years. In 2007 the annual death rate was 4.0% (a total of 49 deceased patients).

The previously given COPD diagnosis was re-evaluated (Figure 1). This evaluation led to exclusion of the following groups of the patients: those who had only fragmented and insufficient documentation (N = 18), those without any spirometry data available (N = 28), and never smokers (N = 26). In never smokers the airway obstruction was found to be associated with miscellaneous restrictive conditions such as sequelae of tuberculosis, asbestosis, and thorax malformation. Altogether 23% of the participants had co-existing asthma. In 20 cases, asthma was considered to be the primary diagnosis and diagnosed at least a decade before COPD. These patients were excluded. In the rest of the patients the primary diagnosis was considered COPD combined with asthma like reversibility and the patients were included (N = 167). For the rest of the patients to whom the COPD diagnosis could not be confirmed were misclassifications, or at one time suspected but later excluded COPD cases (N = 13). Thus, the final cohort of 739 patients with smoking related symptomatic chronic bronchitis was included into the analyses.

At diagnosis the following demographic and clinical variables were recorded: age, gender, duration of the disease, body mass index (BMI), current smoking status, pack-years, results of the baseline and post-bronchodilatation spirometry and single breath diffusing capacity corrected by haemoglobin concentration and alveolar volume, common co-existing diseases and symptoms (shown in Table 1).

Disease severity

Among the 739 confirmed cases spirometry was used to determine the severity of the disease. At diagnosis, 95 (13%) patients showed FEV₁ ≥80% of predicted (Figure 2). In 391 (53%) patients FEV₁ was between 50–80%, in 198 (27%) between 30–50%, and in 55 (7%) below 30% of predicted, respectively. According to the GOLD criteria, the majority of the patients belonged to the Stages 2–3 (moderate to severe) (Table 1). In 275 patients the FEV1/FVC ratio was ≥0.7. In this group the majority of the patients (N = 207) remained undetermined according to the GOLD criteria (FEV₁ < 80% of predicted, but FEV₁/FVC ratio > 0.7) even though they were smokers and had shown mainly irreversible bronchial obstruction (FEV₁ change below 12% in a bronchodilatation test/post bronchodilator). The data shows that a significant number of these patients had also restrictive component in their disease. In the group of undetermined patients, the mean FEV₁ was 63% predicted and FEV1/FVC ratio 0.78 (Table 1). The rest of the patients (N = 68) would be assigned to the GOLD previous Stage 0 (chronic bronchitis).

Figure 2 At diagnosis the proportion of men (grey bars) had more severe obstruction than women (white bars).

Special features of female COPD

In the cohort 36% (N = 266) of the patients were women. The women differed to great extent from the men in several clinical characteristics (Table 1).

Health behaviour. All patients had been diagnosed on average 5.5 years before the study intervention (Table 1). While the age distribution at diagnosis revealed no difference between the genders (58 years), pack-years among the female patients were significantly lower compared to those of the men (45 vs. 55 years, p ≤0.0001). Also the BMI index was lower in women than in men (25.6 vs. 27.1, p ≤0.0001). At the study intervention the participants' health related quality of life was evaluated by both a generic and disease specific instrument. Female patients reported more symptoms in their respiratory specific questionnaire (AQ20 score 8.8 vs. 7.9, p = 0.03) while the generic HRQoL did not differ between genders.

Severity and subphenotypes of COPD. Women displayed less severe bronchial obstruction than men (Table 1, Figure 2). FEV₁ (% of predicted) was > 80% in 20.9% of the women and in 14.3% of the men, between 50% and 79% in 58.2% of the women and in 55.3% of the men, between 30% and 49% in 17.3% of women and in 23.3% of men, and finally < 30% in 3.6% of women and in 7.0% of men (p ≤ 0.002).

Despite the less severe obstruction, DLCOcVA was significantly more severely impaired in women (72.4% vs. 78.0%, p = 0.02). In both genders FEV₁ (% of predicted) correlated with the DLCOcVA (% of predicted) (correlation co-efficient 0.47 in women and 0.28 in men, p for the both correlations ≤0.0001) (Figure 3). In females the correlation, however, was significantly stronger than in men shown by linear regression analysis for an interactive term gender/FEV₁ (p = 0.02).

Figure 3 The correlation between FEV₁ (% of predicted) and DLCOcVA (% of predicted) was significantly stronger in women than in men.

In COPD, the obstruction overlaps with asthma like reversible airway obstruction and lung parenchymal damage causing impaired gas transfer (Figure 4). The distribution of the three main components of the disease was significantly different between the genders (p = 0.01). The proportion of females who had obstruction combined with diffusion capacity impairment (DLCOcVA ≤ 65% of predicted) was increased compared to their male counterparts (29.2% vs. 21.3%). The same trend was also found in women who had simultaneous asthma, like reversibility (25.5% vs. 21.3%) or all three components of the disease (9.5% vs. 4.3%).

Figure 4 The distribution between COPD phenotype components irreversible, asthma like reversible airway obstruction, and impaired diffusion (DLCOcVA < 65% of predicted) in the cohort.

Common co-morbidities: The profile of co-morbidities differed between genders. Overall, females suffered less from other co-existing diseases than men. Only psychiatric diseases, mainly depression, showed a tendency to be more common among the females (13.2% vs. 8.7%, p = 0.06) while cardiovascular diseases, diabetes, and alcoholism were significantly more common among men (Table 1).

DISCUSSION

This study provides real world insight into the complexity of COPD in an un-selected hospital based patient population. The analysis is focused on the specific features of women and men at diagnosis. In several respects the gender gap in COPD is comparable to the situation in cardiovascular diseases. The cardiovascular health of women that has not improved as rapidly as that of men ([16]). The present prevalence based COPD cohort (N = 739) revealed several significant gender dependent differences in clinical outcomes that need be taken into consideration in COPD management. Even though the women had smoked less, they had developed more severe parenchymal disease than men, especially in proportion to the degree of bronchial obstruction. The women reported more frequently respiratory symptoms that worsened their quality of life. Compared to the men, women were less frequently overweight. There were significant differences in gender related co-morbidity profiles. The gender related features obtained from this study partly differ from earlier findings which generally have been derived from specific groups of COPD patients.

Our results extend earlier observations about the importance of COPD definition ([17]). Lately the most widely used COPD definition is the GOLD criteria ([9]) (www.GOLD.com), which uses a fixed post-brochodilator FEV₁/FVC ratio for COPD definition. This leads to an underestimation of COPD in young adults and conversely, overestimates the incidence of COPD especially in older non-smoking age groups (17–20). GOLD criteria have been generally used in population based studies with the above mentioned limitations. Their usefulness has not been widely shown in clinical surveys with different COPD severities. The present study highlights the high number of obstructive patients with a combination of a restrictive impairment of FVC and a FEV1/FVC ratio > 0.7. These patients remain unclassified suggesting that a significant proportion of COPD goes underdiagnosed in hospital based cohorts (Table 1). We performed the same clinical comparisons also by excluding the group of the patients who remained undetermined by GOLD criteria, and found no clinical determinants that would differentiate this group from the rest of the patients (data not shown).

In the present study, the women had smoked less and they showed less severe bronchial obstruction than men, but they suffered more severe impairment in their diffusion capacity. The correlation between airway obstruction and diffusion capacity was stronger in women than in men. These results suggest that the severity of female COPD might be underestimated if we use only the GOLD criteria. That might also explain the constant finding that women report more symptoms ([21]) and suffer dyspnea more often than men ([7]).

Contrary to our findings, some previous studies suggest predominance of bronchitis in women and emphysematous predominance in men ([3],[4],[10]). Our results are in line with a recent Japanese study ([22]), which showed only weak correlation between these parameters but the extensive variation in the severity of emphysema in all stages of COPD and the variations in emphysema even in patients who were at same stage of COPD as defined by GOLD criteria. Our results cannot be directly compared with the conclusions of the NETT study either ([10]). That study evaluated only severe and very severe cases of COPD. Lung parenchyma assessment was performed by HRCT which indicated that women suffered less severe emphysema ([4]). However, when the diffusion capacity was compared in the same cohort, women showed slightly more impaired gas exchange rates than men (N = 1053, DLCO of predicted 27% in women vs. 29% in men, p = 0.0005)([4]).

The same gender difference has been also reported in a COPD cohort representing mild to severe COPD patients (N = 100, DLCO 72% in women 87% in men, p = 0.02) ([23]). Unfortunately a recent study (N = 396) reporting that women had more CT emphysema than men in all severity stages did not report diffusion capacity results for comparison ([24]). Before final conclusions can be made the changes need to be based on different COPD severities using HRCT and diffusion capacity approach, not only severe/very severe cases and on carefully defined COPD diagnosis.

Even though the etiology is unknown, several studies indicate anxiety/depression to be more common in women with COPD than in those male counterparts ([25]). Individuals with COPD display a number of other co-morbidities including heart disease, metabolic syndrome, diabetes and osteoporosis (reviewed by Fabbri et al., Agusti and Soriano ([26],[27])). The present findings suggest that women with COPD may be more vulnerable to psychiatric illnesses while many other co-morbidities such as vascular disease are more common in men with COPD. Overall, the present findings about dyspnea are very consistent with previous investigations though for a number of reasons two of the most important being underdiagnosis and hormonal differences, the prevalence of co-morbidities in women with COPD needs to be clarified in greater detail.

The present study represents a unique patient cohort rich in longitudinal diagnostic information. Since one of our long term goals is to use rich phenotypic data in clinical validation of genetic markers, the study approach clearly showed the heterogeneity of a single ICD category and the potential benefits of valid diagnostic data. This patient cohort is not designed to represent a random sample of the Finnish COPD patients. All participants were identified from the university clinics. They represented all severity stages of COPD, but show evidence of ‘difficult to treat’ -patient population with several co-existing diseases and medications. Due to complexity of the study approach including DNA sampling, and incorporation of health care information from several sources over the period of 10 years to develop a truly comprehensive longitudinal patient profile is decreasing the recruitment rate and causing a further bias in the survey. The ICD number also identifies the cases in which COPD was suspected at some point, but the diagnosis remained more or less open. These cases were found also among the responders (12%) and could decrease the recruitment rate.

Several ongoing Finnish epidemiological studies give us the opportunity to compare clinical characteristics of the COPD cohort to large, age and gender-adjusted general population samples and adjust our findings. This study will continue as a prospective follow-up, and will produce continuous data and thousands of patient years on disease progression providing the opportunity to evaluate not only the outcome and its predictors but possibly also to increase our understanding about the surrogate markers of this disease. The data may finally identify differences among patients in health care utilization and treatment protocols and provide useful markers for monitoring disease progression.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

ACKNOWLEDGMENTS

The authors would like to thank clinical research nurses Ms Kerstin Ahlskog, Kirsi Sariola, and Päivi Laakso for their skilful patient recruitment, Ms Tuula Lahtinen for the monitoring of the project, BM Julia Carlson the analysis of lung function data, and the former personnel of Geneos Ltd for the planning, and implementing the patient recruitment. This study was supported by the funding of Helsinki University Hospital (HUS EVO), University of Helsinki, Foundation of the Finnish Anti-Tuberculosis Association, and Yrjö Jahnsson Foundation.