5 e-Letters

published between 2017 and 2020

  • RE: Biological effect of tissue plasminogen activator (t-PA) and DNase intrapleural delivery in pleural infection patients

    We are grateful that scientists around the world are showing interest in our research, and delighted to reply to comments from Creaney et al. with regards to our paper the “Biological effect of tissue plasminogen activator (t-PA) and DNase intrapleural delivery in pleural infection patients”.[1]
    Pleural infection is a significant clinical entity, has increasing incidence worldwide and is associated with high morbidity, mortality and burden to healthcare services. Effective treatment still relies upon effective pleural fluid drainage, and thus investigation of the pathological mechanisms behind fluid formation and treatment response is key to improving care.
    The MIST2 study demonstrated that intrapleural delivery of tissue plasminogen activator (t-PA) alone or t-PA plus DNase increased volume of pleural fluid drained in humans with pleural infection, in a placebo controlled double blind randomised study.[2 ] Although the exact biological mechanisms via which t-PA induces the volume increment of drained pleural fluid are unknown, the design of the MIST2 study means that we are confident in the biological observation of increased fluid production in response to t-PA administration. Lansley et al. have demonstrated that the chemokine MCP-1 (also known as CCL-2) is the key protein that upon intrapleural t-PA administration induces fluid formation in healthy mice.[3]
    We designed a study to directly assess their hypothesis in human pleural infection patients fo...

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  • Induction of monocyte chemotactic protein-1 by intrapleural instillation of tissue plasminogen activator

    Monocyte chemotactic protein (MCP)-1 has raised interests concerning its role in pleural
    fluid formation. Recent preclinical studies have found that antagonists against MCP-1
    reduces formation of malignant pleural effusions from lung cancer1 and mesothelioma as
    well as from benign (carrageenan-induced) pleuritis2 in murine models. In humans,
    longitudinal collection of malignant effusions via indwelling pleural catheters also showed a
    rise in MCP-1 level over time.3

    In humans and animals, pleural instillation of fibrinolytics such as tissue plasminogen
    activator (tPA) consistently generates large volume of pleural fluid formation in healthy as
    well as in various pleural disease states4, 5. In mice, MCP-1 antagonists also decrease tPA-induced
    fluid formation.6

    We therefore read with interest the work by Kanellakis et al7 on measuring MCP-1
    concentration in pleural fluid samples collected from patients in the MIST (Multicentre
    Intrapleural Sepsis Trial)-24 who were given tPA or placebo.

    The study by Kanellakis et al7 highlights the challenges and limitations of using clinical
    samples/data to decipher biological signals. They reported that following tPA installation,
    MCP-1 level in pleural fluid increased. However, the pleural fluid MCP-1 levels were similar,
    and not significantly higher, in the tPA-treated patients compared with those who did not
    receive tPA.

    We sug...

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  • National COPD Collaborative in Progress in Ireland (Response to Morton et al (2019) paper)

    We read with interest the recent study by Morton et al. A “National COPD Collaborative” quality improvement (QI) initiative (The Collaborative) which is currently on-going in Ireland is also evaluating the efficacy of bundles, amongst other interventions, in improving COPD care. Running from September 2018 to December 2019, the Collaborative comprises 18 consultant-led teams in 19 hospitals across the country working to improve care for patients presenting with an acute exacerbation of COPD (AECOPD). The Collaborative is being run by the Royal College of Physicians of Ireland (RCPI) in conjunction with the Clinical Strategy and Programmes Division of the Irish Health Service Executive (HSE) and the National Clinical Programme for COPD within the HSE.
    COPD is a major health burden in Ireland, as in the UK; based on the 2011 census (total population 4,588,252 [1]), it is estimated that at least 440,000 people in Ireland have COPD (of whom over 180,000 have moderate or severe disease) [2]. In 2015, Ireland had the highest rate of COPD hospital admissions out of all OECD countries [3]. The cost burden of COPD on the HSE is substantial; in 2014, the total cost of COPD hospitalisations was €70,813,040.00 [4]. According to the OECD, the average length of hospital stay (LOS) for COPD in Ireland in 2017 was eight days[5].
    Prior to the initiation of the National COPD Collaborative, treatment of AECOPD within the acute Irish healthcare setting was highly varied; many a...

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  • Airway clearance adjuncts in COPD

    We thank the authors for their interest in our paper (1) which was designed, among other things, to be a statement of intent regarding the need to improve the evidence base concerning the use of adjunct devices for sputum clearance in patients with COPD.
    The authors reiterate some limitations of the data that we had outlined in our paper. In particular we are not able, using prescribing data, to capture other pathways through which patients may have obtained devices, including purchasing them from pharmacies. Direct patient surveys would address this as might company or pharmacy data on sales, if available. We did however present data on actual use of devices, reported by survey respondents, who were mostly in hospital practice, in the preceding year (Table 3). This confirms that use of devices for COPD patients was at an extremely low level and does not support the idea that a large amount of in hospital prescribing, not captured by prescription data, has been missed. We agree that some of the huge disparity with the use of mucolytic agents may reflect overuse of those medications. Nevertheless, the central point, that current extremely limited use of these devices in COPD patients seems at odds with the likely prevalence of patient phenotypes which are believed to benefit, stands.
    At present, this subject is largely ignored in clinical guidelines (2,3). Attention will be needed to address the limited evidence base and so feed into clinical guidelines and cli...

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  • Airway clearance technique prescription in COPD: unmet need or unclear data?

    It was interesting to review the findings of the study by Barker and colleagues [1] regarding airway clearance techniques (ACTs) for patients with chronic obstructive pulmonary disease (COPD). The authors suggest there may be a relative ‘under-prescription’ of simple adjunctive therapy options such as oscillatory positive expiratory pressure (OPEP) devices for the care of this patient group and reflect on the ability for ‘actual use’ registry data to inform research questions in this area. The data certainly show OPEP devices to be used less frequently and at significantly lower costs than prescription medications such as Tiotropium and Carbocisteine. This is not surprising, and is a likely accurate reflection of clinical practice.

    Identification of the most important clinical question(s) to arise from this data, however, appears quite challenging owing to significant limitations that may have been under-emphasised. The true incidence of OPEP device use amongst patients with COPD will certainly have been underestimated in the data obtained from the OpenPrescribing.net resource due to the ‘hidden’ market related to private or hospital-based device purchases. While this is acknowledged by the authorship team, we feel this may be more significant than that proposed. Our experience as clinical physiotherapists working in this area suggests a large proportion (if not the majority) of airway clearance therapy is the remit of physiotherapists working in cardiorespiratory...

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