Background
It is well recognised that patients may develop pleural effusions following coronary artery bypass graft (CABG) surgery [
1‐
3]. Between 65 and 89% of CABG procedures result in the development of a pleural effusion, however most resolve spontaneously or with medical management [4}. The underlying aetiology of these effusions may be independent of the surgery or related to it. Pleural effusions occurring after CABG are divided into early (< 30 days post-surgery) or late (> 30 days post-surgery) [
4,
5]. Late effusions can be subdivided into those with a clear medical cause, such as cardiac failure or infection, and those without, and are much less studied than early effusions [
2]. The pleural fluid in late occurring effusions, characterised in a 26 patient series, tends to be a lymphocytic exudate with normal glucose levels and lactate dehydrogenase (LDH) levels similar to the upper level of normal serum value [
6].
The pathophysiology of the post-CABG pleural effusion is not well understood. It is postulated that the physiological insult of surgery may result in an inflammatory state [
7]. This theory is supported by the finding of pro-inflammatory mediators such as interleukin-6 (Il-6) in pleural fluid in the post-operative phase [
8]. Transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) have been found to rise sequentially in pleural fluid in the perioperative period [
9], suggesting an inflammatory cascade leading to altered pleural permeability, in turn resulting in pleural effusion formation. The influence and persistence in pleural fluid of VEGF is pertinent given its role in angiogenesis and vascular permeability [
10]. Persistent post-CABG effusions have been observed to lead to diffuse pleural thickening (DPT), with corresponding histological evidence of chronic inflammation [
11,
12].
Asbestos is known to cause lung and pleural injury and is associated with a variety of thoracic pathologies driven by inflammatory processes [
13,
14]. Unpublished observational data from a large tertiary pleural centre suggests a possible correlation between asbestos exposure and the development of late onset post-CABG pleural effusion. The authors wished to explore this association further and ascertain if such a correlation could be observed in a national dataset. As both post-CABG pleural effusions and asbestos related lung disease appear to have inflammatory pathogenesis it is possible that previous asbestos exposure may confer an additional risk by ‘priming’ the pleural space prior to the additional inflammatory insult in the post CABG period. A similar effect has been postulated in the development of DPT following transudative effusions, and in bromocriptine-induced pleural effusions in asbestos-exposed individuals [
15,
16], and DPT has been noted to be associated with increased rates of CABG surgery than in the baseline population [
17].
Discussion
Although the use of asbestos was banned in the UK in 1999, many workers were exposed prior to this ban and more recently due to asbestos in the fabric of existing buildings being disturbed. This study explored the association between post-CABG pleural effusion and asbestos exposure. No other published work has addressed this question using such a large prospectively collected dataset.
The HES dataset allows for review of very large numbers of patient records. The population of 69,860 is an accurate number of patients who had undergone CABG surgery in the NHS in England for the time period 2013–2018, due to dataset design.
The demographic data of the study patients is in line with the age and sex of the general population. The higher incidence of asbestos exposure in males compared to females (n = 1003, 97%; n = 32, 3%) reflects the male predominance of asbestos-related disease [
24]. Smoking status has not been evaluated in this study therefore it is not known whether the identified population reflects general population smoking trends. Type of CABG surgery undertaken across both groups is similar, although internal mammary artery connection is lower in the asbestos-exposed population, despite being the ‘gold standard’ approach were feasible [
26,
27]. This reduces the potentially confounding influence of internal mammary artery usage, an approach associated with post CABG pleural effusion [
25]. Internal mammary artery use is associated with a higher degree of morbidity and complication in females thus the approach is more frequently performed in males [
25,
26].
Multiple authors have reported an association between late post-CABG pleural effusion and internal mammary artery graft usage [
2,
27‐
29]. This is thought due to operative interruption of the pleura to access and utilise the vasculature. However, a retrospective study of 410 patients that found no difference in the rate of post-CABG pleural effusion in patients with internal mammary artery connections compared to those with saphenous vein grafts (SVG) [
29].
Asbestos exposed patients are distributed throughout IMD deciles. Historically, occupations that lead to asbestos exposure were predominantly manual or ‘blue collar’, such as pipe laggers, shipyard workers and foundry workers. However, the even distribution of these patients suggests that individuals of all socioeconomic classes and occupations have been exposed to asbestos. This is in line with the observed shift in some countries towards institutional and ‘legacy’ asbestos exposure, with higher rates seen in professions such as teaching and elections [
30,
31]. In contrast however, the strongly male (97%) preponderance for asbestos exposure is in line with established knowledge of asbestos exposure [
32].
All outcomes from this study demonstrate modest increases in odds of development of a post-CABG pleural effusion in patients with documented asbestos exposure. Outcome 1, designed to capture as many patients as possible who have any record of a new pleural effusion diagnosis or procedure in the period of interest, revealed a crude odds ratio (OR) of 1.78 (95% CI 1.37–2.32; p < 0.001) and an adjusted OR of 1.35 (1.03–1.76; p = 0.04) for development of pleural effusion following asbestos exposure. This suggests that asbestos exposure is associated with a moderately higher risk of developing a post-CABG pleural effusion over those who are unexposed.
This finding is mirrored in Outcome 2, in which only procedures associated with pleural effusions are recorded. The crude OR demonstrated was 2.19 (1.51–3.17; p < 0.001) and adjusted OR was 1.66 (1.14–2.40; p = 0.01). This shows a stronger association between asbestos exposure and pleural effusion development, although the confidence intervals obtained are wider in this population. This is an expected finding and correlates well with supporting literature [
27,
29].
The analysis focussing only on codes J61 and J92.0 produced the strongest evidence of risk association, with an adjusted OR of 2.16 (1.38–3.37; p = 0.002). In this group of patients, whose diagnostic codes reflect a sufficient degree of asbestos exposure to cause radiographic changes such as plaques or asbestosis, the odds of post-CABG effusion development is more than doubled compared to the control population.
The sensitivity analysis excluded 12,479 patients with no record of hospital admission in the three years prior to CABG. Due to the lack of hospital records it is impossible to define whether they have been exposed to asbestos or not. It is acknowledged that this approach may result in overestimation of the true rate of asbestos exposure. Outcome 1 in this group demonstrated a crude OR of 1.72 (1.32–2.24 p < 0.001) and adjusted OR of 1.35 (1.03–1.77 p = 0.03). For outcome 2 the crude OR was 2.12 (1.47–3.08 p < 0.001) and adjusted 1.65 (1.14–2.40 p = 0.01). These are very similar to the outcomes from the original analysis however the confidence intervals are wider, reflecting the smaller patient numbers and limiting the interpretation of these results. Nonetheless, they add weight to the association between asbestos exposure and post-CABG effusion. This sensitivity analysis excludes a large number of the ‘healthy’ population by excluding patients with no hospital attendances in the three years prior to CABG. Although this approach may generate a more representative incidence of asbestos exposure in the study population, it necessarily skews the population towards higher impact health service users with inherent higher degrees of illness and co-morbidity.
The frequency distribution of pleural effusion development over the 12 months post CABG is in keeping with the post-surgical effusion development hypothesis, rather than reflecting benign asbestos related effusion (BAPE) development. By excluding any mesothelioma diagnoses from the data we have significantly reduced the risks these pleural effusions have a malignant aetiology.
The proportion of procedures performed on patients in this study appears to fall in favour of chest drainage (n = 552) rather than pleural aspiration (n = 353). However, 209 patients are coded as having under gone ‘drainage of pleural cavity NEC’ and 26 ‘other specified puncture of pleura’. Whilst ‘drainage of pleural cavity NEC’ is likely to represent chest tube drainage rather than aspiration, this cannot be confirmed therefore it is not possible to interrogate these numbers further. Allowing for these 235 patients, the skew in favour of chest drainage likely represents both a larger number of symptomatic effusions and a potential reticence to perform aspirations on small effusions. Clinical experience suggests that small, asymptomatic effusions are not always be aspirated in the setting of CABG follow up - the treating clinician may feel the diagnosis is clear and no fluid analysis required.
This study has limitations that must be acknowledged when interpreting results. As a retrospective analysis, this work may only describe associations rather than causality. The relatively low numbers of patients identified and modest effect size should also be borne in mind by the reader when interpreting our findings.
Although the HES dataset allows for analysis of huge numbers of patient records, the way that the data is recorded and the manner in which clinical coding is undertaken in England result in inconsistent data capture for many medical procedures, especially those carried out during an inpatient admission – the details are often recorded in complex medical notes that may be missed by clinical coders. Elective surgical admissions, outpatient episodes and procedures result in better data capture due to the manner in which hospitals in England derive revenue streams. Subtle medical diagnoses and risk factors such as asbestos exposure may be incompletely and inconsistently recorded in medical notes and coding episodes. Therefore the HES dataset is likely to under-report the true number of patients with asbestos exposure and also may under-report the number of patients with pleural effusions requiring intervention. As the HES dataset is primarily a coding repository, clinical information such as test results are not recorded, therefore this study is unable to analyse clinical information including biochemical parameters of pleural fluid and imaging findings.
The HES dataset does not allow for the sizing of the effusions to be analysed, nor does it record the underlying aetiology. Thus it is not possible to guarantee that all reported effusions are post-CABG in origin. The exclusion of patients who had a diagnosis of pleural effusion in the 3 month prior to CABG reduces the probability of capturing an effusion due to another aetiology. Selection criteria for CABG surgery will also exclude patients with conditions such as malignant pleural effusion. Therefore, the authors believe that the vast majority of the pleural effusions reported in this study represent post CABG effusions, however this cannot be quantified. Allowing for this, the data reported here still show an increase in the incidence of pleural effusions of all causes in those with previous asbestos exposure.
Interpretation
The results of this study show that there is a modest association between asbestos exposure and post-CABG pleural effusion. Asbestos exposure has been demonstrated to confer an adjusted OR of 1.66 for the development of a pleural effusion requiring intervention in the period 30 days − 1 year following CABG. This association is reflected in all analyses performed, albeit with variation in OR value and confidence intervals. In patients with radiological evidence of asbestos exposure (pleural plaques or asbestosis), the OR is 2.16 – representing a doubling of risk compared to unexposed patients. The study findings correlate with anecdotal experience from asbestos disease specialists and suggest a potential link between asbestos exposure and the development of last onset post-CABG pleural effusions. The possibility of shared inflammatory pathogenesis, with asbestos mediated ‘priming’ of the pleural space is raised. Finally, this study demonstrates the utility of the HES dataset in providing data for large scale study of relatively rare conditions that may not be adequately captured in local registries.
Further work using prospective collected detailed asbestos exposure data, chest radiograph analysis and pleural fluid analysis is now required. Additional clinicopathological studies are also needed to explore the aetiological links between the two entities.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.