296 e-Letters

  • Prospective randomised controlled trial: fixed 1-year screening interval group versus a tailored intervals group

    In 2011, the National Lung Cancer Screening Trial (NLST) showed that annual low-dose computed tomography (LDCT) improved overall survival (1). More recently, longer interval between LDCT rounds was advocated to improve screening efficiency after baseline (2).
    Schreuder et al reported a comprehensive model for optimization of LDCT by biennial rounds for subjects at lower 2-year risk of lung cancer (3). They built a promising polynomial model including both patient characteristics and nodule descriptors. The retrospective simulation on NLST data provided enough power to test Schreuder’s model (3) as well as other models for selection of subjects to be forwarded to biennial screening (2, 4). We appreciate this approach to parsimonious LDCT administration as we are strongly convinced that annual screening should be tailored to subjects with remarkably high risk of lung cancer. The authors refer that prospective randomized controlled trial with tailored screening intervals would be hardly feasible, however we would like to remind that some experience was already reported in the literature.
    Since 2005, the Multicenter Italian Lung Detection (MILD) trial conducted a prospective comparison between annual (LDCT1 = 1,152 screenees) and biennial LDCT (LDCT2 = 1,151 screenees) (5). The LDCT2 screenees were shifted to annual screening in case of solid nodule > 60 mm^3 and/or subsolid nodules. In other words, the MILD trial prospectively tested a risk model for tailored s...

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  • Comparison of ICS doses

    We are grateful to Dr. Duerden and Dr. Levy for their comments on our paper which highlight the difficulty of comparing doses of ICS steroids when there is no gold standard comparator. Our aim in compiling Table 1 was to point out that the NICE table does not allow for the greater potency of HFA FP compared to HFA BDP. We were concerned that this was a significant safety issue especially in children [1]. In our efforts to simplify this message, we had not fully explained or allowed for some of the other variables.

    1. Dr. Levy is correct to point out that the original GINA table (used by NICE) of “Low, medium and high daily doses of inhaled corticosteroid for children 6-11 years” has a statement below indicating that the table is not a table of “dose equivalency”, the term we used in Table 1, but of “estimated clinical comparability”.

    2. The GINA table (but not NICE) also has a footnote explaining the inclusion of beclometasone dipropionate CFC (BDP CFC) as a comparison with older literature. CFCs (chlorofluorocarbons), as propellants in metered dose inhalers, were phased out under the Montreal Protocol and were replaced by HFAs (hydrofluorolakanes). However, CFC BDP is still often used as the reference standard when comparing ICS in terms of their potency.

    3. Most newer HFA ICSs have been formulated to be equipotent with the CFC ICS they were replacing. As one example, the BTS/SIGN table includes the proprietary HFA BPD, Clenil modulite, commonly us...

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  • Contact screening in TB: is it time to re-brand?

    We welcome the letter by Anna Humphreys and colleagues highlighting the secondary benefits of screening contacts of extra pulmonary tuberculosis for LTBI in areas where active cases are predominantly amongst the non-UK born (1). 
    We share the view that novel approaches are needed to identify and offer testing to those at risk of LTBI, and that contact tracing provides a unique opportunity to reach those who may be eligible.  

    Early results from the London Borough of Newham, the pilot site for the national latent TB screening programme highlight that uptake of LTBI screening amongst recent migrants is only 40 percent (2). Efforts are being made to improve awareness including animated health promotion tools (https://youtu.be/tKwAHJ7JeV0) and TB Alert’s Latent TB Handbook (https://www.tbalert.org/health-professionals/ltbi-toolkit/) and novel interventions to improve LTBI screening and treatment uptake are being implemented across the country. We are currently investigating the efficacy of managing LTBI entirely within primary care (https://clinicaltrials.gov/ct2/show/NCT03069807). Recent work has also identified that opportunistic LTBI screening in non-health settings is acceptable to recent migrants (3).
    In areas where the majority of active cases are amongst those...

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  • What does the EPICC trial really tell us?

    We have read with great interest the multi-centred EPICC trial that randomized over 300 patients [1]. While the delivery of a complex physical rehabilitation intervention in clinical trials is difficult, we believe that several aspects of the trial may have resulted in the inability to detect a difference between the control and intervention groups. These factors include the delayed time to start the intervention, inadequate delivery of the intervention and the large loss to follow-up for the primary outcome measure. In our opinion, these three factors limit the interpretation of the results of the study. While the authors have mentioned some of these concerns in their discussion, and Connolly et al. raised some of these points already [2], we hope to learn some important lessons from the authors to better understand these limitations and how they can be minimized in future studies.
    The number of randomized controlled trials evaluating early physical rehabilitation in ICUs is increasing [3]. Positive effects on primary outcomes were only found in studies in which physical rehabilitation was started within 72 hours of ICU admission [4-6]. Studies, which did not meet this criterion of early onset of physical rehabilitation, did not demonstrate benefit of the intervention [7]. Therefore, this time frame has been defined in rehabilitation guidelines [8]. Based on this evidence, we are not surprised that the authors of the EPICC trial were unable to demonstrate beneficial...

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  • Smoking duration, smoke intensity or pack-years: what is the best method for exposure ascertainment?

    The article of Bhatt et al addresses an important topic (1). The authors assessed the relative contribution of intensity and duration of tobacco smoke exposure to the development of chronic obstructive pulmonary disease (COPD). They concluded that smoking duration alone provides stronger risk than the composite index of pack years. In other words, the effect of long and low intensity exposure has a stronger association with COPD than short exposures of high intensities. The article of Marks consents this finding, concluding that pack years are a suboptimal index of exposure (2).

    A major limitation of the study of Bhatt, which surprisingly is not stated as such, is the use of a cross-sectional design that does not allow drawing causal conclusions. The conclusions drawn therefore might be flawed.

    Selection bias due the healthy ‘survivor’ effect might have occurred. The duration of smoking could have been influenced by the deleterious effects a person experiences from the exposure to smoke. Those with a long smoke duration are more likely not to experience (or experience less) health issues due to smoking, and might therefore have less severe (or no) COPD than those with a short smoke duration. In line with this, selective ‘drop-out’ of the more diseased persons may have biased the results.

    Furthermore, the authors use retrospective data, while this often leads to recall bias. Participants often do not precisely remember the numbers of cigarettes smoked...

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  • Macrolides and Mycobacterium abscessus - time for a rethink?


    We read with interest the latest BTS guideline for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).1
    Of particular interest was the section relating to the treatment of Mycobacterium abscessus –pulmonary disease. The evidence for the treatment regimes remains poor (Grade D) and within paediatric population the experience of treatment strategies is based on both adult guidelines and clinical expertise. Questions remain about the rationale for the use of macrolides in organisms with inducible resistance. Table 8 in the article recommends the use of oral macrolides during both induction and continuation phase even if inducible macrolide resistance has been demonstrated in vitro. By definition, M. abscessus abscessus strains will possess a functional erm(41) gene, 2 and therefore we feel use of this drug may be inappropriate for this subspecies.

    Azithromycin is a bacteriostatic antibiotic, with intracellular penetration superior to that of the aminoglycosides. 3 M. abscessus complex can thrive within the intracellular environment. 4 Given the exposure of intracellular M. abscessus abscessus to a bacteriostatic agent we suggest this may induce not only resistance but also quiescence within the bacterium and therefore the bactericidal action of aminoglycosides would be significantly impaired given the lack of active protein synthesis. This quiescent state is likely given the difficulty in isolating this organism whilst the...

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  • Inaccuracy regarding Inhaled Corticosteroid equivalence

    While I agree this paper draws out most of the important issues related to the NICE guideline, I would like to point out that there are inaccuracies regarding the statements and table related to 'dose equivalences' in the GINA document.
    In fact reference to equivalence in your article is explicitly contradicted by the statement immediately below GINA table 3-6, which states that 'this is not a table of equivalence, but of estimated clinical comparability'. (1)
    Furthermore the GINA table also takes into account the potential for side-effects. For example, BDP HFA causes more adrenal suppression than FP HFA at the same dose. (2)
    Of course this is going to get even more complicated with the number of generics now available, as they cannot be assumed to be equivalent to the original product, due to the impact of the inhaler device and additives.

    (1) www.ginasthma.org
    (2) Fowler, S. J., Orr, L. C., Wilson, A. M., Sims, E. J. and Lipworth, B. J. (2001), Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate. British Journal of Clinical Pharmacology, 52: 93-95. doi:10.1046/j.0306-5251.2001.bjcp.1399.x

  • Opioids for the palliation of breathlessness Cochrane review: additional analyses yield same conclusions

    We thank Associate Professor Magnus Ekström et al for their research letter regarding our Cochrane Review: Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness (1,2). We also acknowledge that following the publication of their letter in Thorax, feedback was provided through the appropriate mechanism to the Cochrane Review Group (2). We have published a detailed response to their comments in the feedback section of our review, however, given the seriousness of the criticisms published in Thorax, we think it is important that our response also sit alongside their Thorax letter.

    We acknowledge the statistical difficulties in the interpretation and summation of the complex data on opioids for breathlessness. One such issue is the inclusion of crossover studies in a meta-analysis, however, a crossover design is an appropriate way to assess short term interventions, particularly when patient recruitment may be challenging. The Cochrane Handbook outlines several methods to incorporate crossover data into meta-analyses (3). In using the data as if it was a parallel study, the limitations should be acknowledged, in that it can give rise to a unit of analysis error whereby confidence intervals may be wide, and the overall effect is under-estimated. An alternative method is to calculate correlation co-efficients (which describe the ratio of between-patient standard deviation with the within patient variation) to impute...

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  • Modernising scientific careers in the NHS: capacity building to improve training in pulmonary physiology and the interpretation of lung function tests.

    We read with interest the timely editorial by Gerrard Phillips (1), concerning the importance of providing physiological training to trainee respiratory physicians. This reviewed a French study indicating that trainees who had received an internship in a respiratory lab were substantially better at diagnosing respiratory abnormalities compared with trainees without such training. (2) Dr Phillips made a persuasive, “essential” case for an integrated understanding of respiratory physiology/pathophysiology, lung function testing and interpretation in clinical trainees.

    We strongly agree and also argue that the problem is the recognition of the importance of physiology in general, across the specialist service. We are involved in work that aims to build physiologist numbers, leadership and lab capacity, and feel this could lead to improved training for trainee doctors, as has been shown in the audit of French trainees (2). This would very much benefit from further support from colleagues and hope that the following information helps to make this case.

    In December 2015 the first NHS physiology scientist students of the new national NHS Masters in Respiratory medicine graduated from Newcastle University. This course is part of the national Modernising Scientific Careers (MSC) program in the NHS. The respiratory teaching faculty is consultant led, with delivery in hospital clinical teaching facilities.

    Modernising scientific careers (MSC) is a UK wide initia...

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  • Pleural sclerosis vs pleurodesis


    Dear Sir,
    In this comprehensive article the authors state that "recurrence prevention involves an attempt at pleurodesis
    ( permanent apposition of the visceral and parietal pleura to seal the pleural space )"
    This is a simple and convincing explanation for any young male suffering persistent or recurrent pneumothorax (or indeed, a patient suffering symptomatic malignant pleural effusion ).
    The histological changes after "pleurodesis" have been widely and clearly described in the literature and universally accepted. ie. fibrin deposition, collagen formation , fibrosis +/- some adhesions.
    However the medical literature seems devoid of descriptions of ablation of the oleural cavity following "successful pleurodesis", at subsequent thoracotomy or post mortem despite the enormous number of such procedures performed since the 1930s.
    This must raise the possibility that such ablation does not occur and that the "clinical success" of the procedure results from the histological changes which are described.
    Are the authors aware of any evidence to support ablation/obliteration of the pleural cavity following this procedure ? Perhaps pleurosclerosis may be a more accurate term