10 e-Letters

  • Response to Dr Wilkinson and Professor Woodcock

    We are grateful to Dr Wilkinson and Professor Woodcock for their comments on our paper.

    A key topic raised is related to the assumptions on the timelines to transition to low-Global Warming Potential (GWP) propellants. As of today, several Companies have committed to substantial investments in metered dose inhalers (MDIs) with novel propellants (1-4), indicating developments are progressing fast to target market introduction over the next few years, with 2025 as suggested initial date, and roll-out across portfolios and geographies. Previous transition from CFC to HFC-containing MDIs represents a precedent experience that can be leveraged to ensure a faster process, also dictated by pressure imposed by evolving regulations of HFC use. The new lower global warming potential propellant used for the inhaler transition in this analysis, HFA-152a, has been under development by Koura for an extended period for use in MDIs for the treatment of respiratory disorders such as asthma and COPD (5). In 2020, Koura reported that the US FDA had approved clinical trials with HFA-152a (6) and that the medical-grade propellant has been subject to an extensive suite of inhalation safety testing (including a chronic two-year pre-clinical study). It is understood that this extensive program will be used to support the future commercial use of medical-grade HFA-152a, with the essential Drug Master File expected to be finalized in 2022 (7). We agree that, in addition, the necessary clinic...

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  • Missed opportunities to improve disease control and unrealistic expectations about novel propellants.

    We are strongly supportive of efforts to reduce the carbon footprint of inhalers. We believe this should be achieved by providing easily understood information to patients and health care workers to be able to make informed decisions about their inhaled treatments. Near term changes prioritising controller medication with the very large range of available Dry powder inhalers (DPIs) could reduce the carbon footprint by 90%, bringing the UK in line with the rest of Europe.

    The paper is essentially written by Chiesi pharmaceuticals. We are concerned about potential bias in the paper arising from this conflict of interest. Chiesi are to be applauded for having committed substantial R&D to the development of metered dose inhalers (MDIs) containing a novel lower GWP propellant HFC-152a to replace high GWP 134a. They are one of only two companies who have announced a transition using HFC-152a for their large range of MDIs.(1,2) However, the paper contains a number of inaccuracies, and is over-optimistic on the timing and pace of transition.

    The timelines for achieving a transition to HFC 152a pMDIs are unrealistic; the transition to HFA152a is likely to take far longer than described in the paper. So far, no safety or efficacy data is available for any inhaler containing HFC-152. No detail on requirements for HFC 152a inhalers has been published by the regulatory agencies, although it seems almost certain that long-term human safety data will be required.(3)...

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  • High LDL-cholesterol protects against infections

    What very few know is that more than a dozen research groups have demonstrated that low density-lipoprotein (LDL) participates in the immune system by adhering to and inactivating almost all kinds of microorganisms and their toxic products.1 For instance, compared with normal rats, hypocholesterolemic rats injected with bacteria have a markedly increased mortality which can be ameliorated by injecting purified human LDL. When covered with LDL, the bacteria accumulate and are phagocytosed by macrophages, which are subsequently converted to foam cells. This fact may explain the finding by Yusufuddin et al.2 that mortality was lower among the patients with pneumonia if their LDL-cholesterol was elevated. The same phenomenon was found in a follow-up study of about 30,000 community-dwelling adults by Guirg et al.: LDL-C was inversely associated with the risk of suffering from one or more sepsis events (Table 1).3

    LDL-C quartiles Q1 Q2 Q3 Q4
    Number of participants 6984 7088 6915 6896
    Sepsis events (%) 451 (6.5) 399 (5.6) 304 (4.4) 261 (3.8)
    Table 1. The LDL-C quartiles of those who suffered from one or more sepsis events
    according to the study by Guirgis et al.3

    That high LDL-C may be protective is also evident from a meta-analysis of 19 studies where the authors had followed more than 68,000 elderly people for several years.4 What they found was that those with the highest LDL-cholesterol lived the longest; non...

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  • Safe, patient focussed, multidisciplinary tracheostomy care should be the goal for Critical Care research teams

    Dear Editors
    We read with interest the scoping review by Whitmore and colleagues into the post-insertion and pre-decannulation management of tracheostomies in the Intensive Care Unit.1 This important work highlights the need and opportunity for research in some areas of the complex management of these vulnerable patients. However, the manuscript has some significant limitations particularly; search strategy; timing; omission of patient safety recommendations; and patient focus; which we discuss below.
    The search strategy is limited to minor variations in the keywords, “ICU”, “Intensive Care Unit” and “Tracheostomy,” which excludes any article with the US “tracheotomy” in the title and international variations in care locations, such as, “Intensive Therapy Unit”, “Critical Care Unit”, “Weaning Unit”, “High Care” and associated abbreviations. The authors themselves refer to “critical care” literature but have omitted this from their strategy. A PubMed search (www.pubmed.ncbi.nlm.nih.gov, 27/8/20) finds 11,553 results for “tracheotomy,” 15,894 results for “tracheostomy” and 25,243 results for “tracheostomy or tracheotomy”.
    Furthermore, whilst the search is necessarily time-limited, there has been a recent surge in tracheostomy literature including relevant publications for managing tracheostomy in the COVID-19 pandemic.2-4 Whilst the results from Whitmore and colleagues are a useful benchmark, we fear that the...

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  • 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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  • Cromoglicate at step 4
    Brian J Lipworth

    The excellent review by Slater et al comprehensively covers options for add on therapy to inhaled steroid at step 4 in patients with suboptimal asthma control .However no mention was made of the possible role for inhaled cromoglicate . This is a drug which appears to fallen out of favour and hardly gets a mention in guidelines . This is perhaps surprising given its excellent therapeutic index especially in children1 . We...

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