305 e-Letters

  • Response to Kennedy et al

    We thank Dr Kennedy and colleagues for their interest in our recent
    paper comparing outcomes after surgery and SABR radiotherapy in
    stage I non-small cell lung cancer (1,2) .
    We agree that intraoperative nodal upstaging can be a cause of stage
    migration in the surgical arm but not the SABR arm, and so could act
    as a potential bias in an observational study. This might
    overestimate the benefit of surgery compared to SABR. The Society
    for Cardiothoracic Surgery Database Project reported 2155 patients
    undergoing lung cancer resections in England from 2014-16, and
    found that over 13% of patients underwent nodal upstaging when
    their resection pathology was analysed (3) .
    The information bias inherent in having full pathological data
    available for surgical but not SABR cases leads to other potential
    problems with analysis. All patients undergoing surgery have a
    pathological analysis confirming the cancer and its stage, while 240
    of the 476 patients treated with SABR were treated without a
    pathological diagnosis. A recent prospective UK study found that
    14% of patients operated on for presumed lung cancer had benign
    disease on intraoperative frozen section biopsy or final pathology (4) .
    Assuming that this surgical false negative rate approximates the rate
    in the suspected early clinical stage patients treated with SABR, then
    around 7% of our SABR arm may...

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  • Response to Laura W Lund, and Jeremy D Kimmel ALung Technologies January 16, 2020

    The SUPERNOVA trial was a prospective observational phase II study supported by an unrestricted grant from three companies (Alung, Maquet, and Novalung) and by the European Society of Intensive Care Medicine (ESICM). The three companies provided equipment and covered costs for data monitoring, site visits, and insurance fees. The grant (€171,000) was made available to ESICM that supported data collection and analysis, and all administrative costs. As owner of the data, ESICM appointed the two principal investigators (AC and VMR) and the independent Data and Safety Monitoring Board (Jukka Takala, Chair). The study included 95 patients. The proportion of patients who achieved ultra-protective settings by 24 hours was 82%. Number of patients that experienced severe and ECCO2R-related adverse events was 2 (2%) and 37 (39%)1. Retrospective analysis of these data showed that (a) efficacy of ECCO2R to facilitate further reduction of tidal volume was lower with smaller artificial lungs and running at lower blood flow than with larger artificial lungs and running at a higher blood flow2; (b) haemolysis and bleeding was higher with the former than with the latter2; (c) applying these data to a previously described theoretical model3 we predicted that incorporating higher CO2 removal rates as factors to design randomized clinical trial might substantially reduce screening and sample size requirements4.
    In her letter, Dr Lund, expressed several concerns about these findin...

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  • Nodal staging should not be left out of the equation

    We read with interest the report from Khakwani and colleagues comparing real-world outcomes for patients with stage I NSCLC undergoing surgery and stereotactic radiotherapy (SABR) (Ref 1), together with the accompanying editorial (Ref 2). Given the failure to recruit to previous randomised trials designed to compare these treatments, analyses of large national datasets are vital to improve our understanding of how best to manage this patient group.

    One additional possible explanation for the worse outcome in the SABR cohort relates to occult nodal involvement. Inaccuracies in clinical staging are well described; one analysis documented that 34% of patients are under-staged by pre-operative work-up (Ref 3). Patients with occult nodal disease would have been identified in the surgical group by intraoperative systematic nodal staging, and would therefore have been excluded from analysis of the Stage I cohort presented here (Ref 1). Patients who are similarly under-staged prior to SABR treatment will remain in the Stage I cohort for analysis, yet will have worse outcomes by virtue of their more advanced disease. Comparing outcomes on an intention-to-treat basis using pre-treatment stage may minimise this bias.

    We agree with the authors that residual confounding may be an important factor explaining these results, and that examination of cause of death is instructive. In our single centre study, cause of death was compared (on an intention to treat basis) between...

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  • Response to "Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study" (Combes et al,, 2019 Dec;74(12))

    Dear Editor,

    We read with great interest the recently published article in Thorax by Combes and colleagues titled “Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study” [1]. In this article, the authors present brief, post-hoc analyses of safety and efficacy data derived from the SUPERNOVA trial, a single-arm, multi-center, pilot study assessing the feasibility and safety of extracorporeal carbon dioxide removal (ECCO2R) to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress syndrome (ARDS) [2]. The study was conducted at 23 centers, each of which used one of three different ECCO2R devices.

    We wish to communicate significant concerns regarding improper categorization of ECCO2R device performance as well as important study limitations impacting interpretation and value of the presented data. The differentiation between devices based on the terms “higher CO2 extraction” and “lower CO2 extraction” is incorrect based on supporting evidence and engineering principles summarized in this letter. In addition, safety data was presented and statistically compared without including available associated data that would bring in to question the implications of the analyses. As the manufacturer of one of the ECCO2R devices used in the SUPERNOVA pilot study, we are strong believers in the life-saving potential of ECCO2R technology and its...

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  • Carbon footprint impact of the choice of inhalers for asthma and COPD. Response to letter from Murnane et al.

    Dear Editor

    We thank Professor Murnane and co-authors for their comments on our paper: “The carbon footprint impact of the choice of inhalers for asthma and COPD” [1]. Unfortunately, there are some misunderstandings in their letter and we are happy to try to resolve them.

    1. Our study was intended to look at a high-level model for carbon savings in respiratory care, using existing device options with recognised limitations for wider application. It is not a blueprint for system change or a fully costed recommendation for health decision makers. We do not think that it is realistic to change the prescribing patterns from the current 70% pMDIs in England to Swedish levels. We do, however, think it is important to illustrate the potential GWP gains that can achieved if the suggestions in the BTS statement on ‘the environment and lung health’ and the sustainability ambitions of NHS England in its Long Term Plan (7) are followed: “Complete elimination of pMDIs may not be possible due to patient preference and the need to generate sufficient inspiratory flow to activate the DPIs. However, BTS encourages all prescribers and patients to consider switching pMDIs to DPIs whenever they are likely to be equally effective.” (5).

    2. The Murnane et al response refers to content which is not in our paper, such as ‘switching pMDIs to the cheapest DPIs’. The paper does not analyse or compare the costs of switching as this is outside the scope of the study. While th...

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  • Reply to 'Patient engagement is vital'

    We thank John White for his letter and wholeheartedly agree that switching of inhalers, for any reason, should solely be done after assessing the suitability of the switch for each individual patient and with full engagement and agreement of the patient. We also thank him for further raising the issue of the environmental impact of inhalers. As he points out, our study found that following a switch of inhalers, there was no deterioration in disease control. It is worth noting that this improvement was found with all switches we assessed, including those switching from MDIs (containing propellants containing potent greenhouse gases) to DPIs (containing low global warming potential). We agree that a potential reason for improved disease control was an interaction between clinician and patient, also explaining the increased adherence. We too have anecdotally come across patients for which switching inhalers for financial reasons appeared to be detrimental to their health; this was the impetus for the study. The study findings were perhaps unexpected, but as epidemiologists, feel this shows the relevance of considering the whole population at risk, and as clinicians, the importance of tailoring interventions to the individual.

  • Carbon footprint, environmental impact, and patient outcomes in inhalation therapy: No simple solution to the complex challenges

    It was with great interest and not a little concern that we read the recent Brief Communication by Janson and colleagues [1] into the impact of pressurised metered dose inhalers (pMDIs) on the global warming potential (GWP) of respiratory care. We note the tenacity of one of the authors who has succeeded in publishing a second paper [2] based on a similar, flawed logic just two weeks later. The sense of proportion that is missing in both reports has, thankfully, been identified in the press this week.[3] However, we feel it essential to scrutinise the current contribution scientifically.

    The authors report the carbon footprints of a range of devices marketed by GlaxoSmithKline (GSK) following analysis undertaken by the Carbon Trust (a UK not-for dividend company). Subsequently, calculations were undertaken aimed to determine how the carbon footprint of inhalation therapy in the UK’s National Health Service (NHS) might be reduced by altering the prescribing patterns of UK physicians (where more pMDIs are prescribed than dry powder inhalers (DPIs)) to resemble those of Swedish physicians (where the converse holds). While we acknowledge the authors’ declaration that their data are potentially flawed by the fact that their calculations are based on extrapolating the carbon footprints of just three device formats manufactured by one company to predict the effects of total DPI and pMDI usage in the UK when the carbon footprints of most other devices are unknown, we wou...

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  • Patient engagement is vital

    This paper provides welcome reassurance that switching of inhalers can be carried out not only without risk of deterioration but that improvements in disease control may be seen. My supposition is that this is due to the interaction between clinician and patient to discuss the switch that stimulates increased engagement in the patient leading to better outcomes. Whatever the mechanism this paper is timely with the BBC just today featuring an article on the environmental impact of inhalers and the need to reduce the NHS carbon footprint by choosing more environmentally friendly options.
    The latest BTS/SIGN national asthma guideline includes new information on this and highlights opportunities to recycle pMDIs where possible.
    However, a word of caution on inhaler switching may be in order. Although only anecdotal evidence from my lengthy clinical practice I have on several occasions met patients from different surgeries who have had their regular inhaled therapies repeat prescription changed without discussion, never mind agreement - usually on cost saving rather than environmental reasons - leading at best to loss of confidence in their local surgery and at worst loss of control of their asthma such that an attack was precipitated leading to hospital admission. This was not only a significant risk for the individual but far more costly than the anticipated s...

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  • To the Editor and to the Authors

    To The Editor and to The Authors.

    I wish to congratulate the authors. I find their review on RSV-induced severe disease attractive in all respects. It impressively presents research ranging from epidemiology to molecular immunology, and includes promising treatment opportunities. My perhaps peripheral comments relate to the authors’ conclusion that “much remains to be discovered regarding the host response to RSV infection”.

    Loss of epithelial cells and pathogenic roles of exaggerated epithelial regeneration.
    I’d like to dwell somewhat on RSV-induced epithelial cell loss, which is mentioned in passing in the review. Bodies constituted of many epithelial cells clumped together in airway lumen material have been named Creola bodies by Naylor (1) who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread patches of epithelial shedding, may also be a prominent feature of RSV infection. Indeed, in RSV-infected infants Creola bodies in aspirates seem to be a requisite for the infection to be followed by development of asthma (2,3). This is of interest because epithelial regeneration processes alone, rather than the reputed increased permeability to inhaled material (which is not observed in vivo in asthma (4)) are causative regarding several facets of airway inflammation and remodelling (5,6).

    Lethal RSV infections in children are associated with extensive and patchy loss of bron...

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  • Variants of VEGF in Congenital Diaphragmatic Hernia and Pulmonary Hypertension

    We have read this vital article, and after reading we would like to agree with the findings of the authors but we would like to suggest a complementary study for future directions. The VEGF gene encodes angiogenic protein and it is located at chromosome 6p21.1. Numerous SNPs in the promoter, 5'-, and 3'- untranslated regions (UTR) VEGF have been reported. Some of the more frequent SNPs involved in major solid tumour are well reported inclusive of rs2025039 (1), rs1570360 (2), rs699947 and rs2010963 (3), rs1570360 and rs8333061 (4). There is a serious need to study the role of these SNPs in congenital diaphragmatic hernia and pulmonary hypertension.


    1. Krippl P, Langsenlehner U, Renner W, et al.A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. International Journal of Cancer2003;106:468–71. doi:10.1002/ijc.11238

    2. Howell WM, Rose-Zerilli MJ. Cytokine Gene Polymorphisms, Cancer Susceptibility, and Prognosis. The Journal of Nutrition2007;137. doi:10.1093/jn/137.1.194s

    3. Jin Q. Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis. Clinical Cancer Research2005;11:3647–53. doi:10.1158/1078-0432.ccr-04-1803

    4. Gupta D, Gupta V, Singh V, et al.Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients. Meta Gene2016;9:249–53. doi:10....

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