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...
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 born in high TB-burden countries, a reinterpretation of contact screening that encompasses the aims of identifying active TB cases, as well as recently and remotely acquired LTBI would allow TB programmes to reach many more people at risk.
The National guidelines were updated based on evidence that non-pulmonary TB is a lower risk for transmission (4). Screening contacts is justified given the public health risk of active disease in those recently exposed and a case can be made for screening contacts of extra pulmonary cases as they may have been infected by a previously unknown pulmonary index case.
However, should we decide to change our approach to screening contacts with the explicit aim of identifying LTBI due to remote infection then we must at least acknowledge this when we talk to patients about their recent contacts and ask them to share personal information. And, as a TB community, we must agree that this approach is ethical.
We would support this broader eligibility for screening contacts and believe it would strengthen an already vital tool in the fight to eliminate Tuberculosis in the UK.
1. Humphreys A, Abbara A, Williams S, John L, Corrah T, McGregor A, et al. Screening contacts of patients with extrapulmonary TB for latent TB infection. Thorax. 2018;73(3):277-8.
2. Loutet M. National Roll-out of Latent Tuberculosis Testing and Treatment for New Migrants in England: a retrospective evaluation in a high-incidence area. European Respiratory Journal. 2017:1-25.
3. Walker CL, Duffield K, Kaur H, Dedicoat M, Gajraj R. Acceptability of latent tuberculosis testing of migrants in a college environment in England. Public Health. 2018;158:55-60.
4. Hoppe LE, Kettle R, Eisenhut M, Abubakar I. Tuberculosis—diagnosis, management, prevention, and control: summary of updated NICE guidance. BMJ. 2016:h6747-9.
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...
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 effects of their intervention, since it approximately started on day 8 (the median (IQR) duration of ventilation at randomisation was 4 (3–7) days with a further 3 (1–6) days until the first physical rehabilitation was received), which may be too late to confer benefit.
The EPICC protocol aimed to compare 30 min vs. 90 min of physical rehabilitation, which was not achieved in either group. The authors report that the daily physical therapy was applied for 23 min in the intervention group (26% of the planned intervention) and for 13 min in standard of care group (43% of the planned standard care), respectively. Not only this amount of physical rehabilitation is hardly conceivable as an effective therapeutic strategy, but in terms of testing the hypothesis, it did not achieve the planned separation between the groups. In other words, the EPICC trial teaches us that an additional 10 minutes of physical rehabilitation per day does not make a difference.
The authors describe two main reasons for not achieving their planned intervention: (a) sedation and (b) patient fatigue. We have difficulties understanding why these two factors could not be controlled. The authors do not report the sedation regime during the study. If there was no standardized sedation protocol with daily awakening trials, this is a further shortcoming of the protocol as well as another reason for inability to improve the patients’ outcome in the intervention group. Deep sedation not only inhibits effective physical rehabilitation but is associated with increased mortality and length of stay [8]. To better appreciate the study results, it would be important that the authors report the sedation protocols/regimes of the participating centres.
Furthermore, how was the treatment plan of the intervention in “difficult” patients with low physical reserve or pre-existing frailty implemented? From our own experience patients with impaired functional reserves or frailty might only be trained for a short period of time. However, to achieve an intervention time of 90 minutes per day, such patients must be trained several times a day (e.g. for 15 minutes every hour). If 23 minutes are achieved in the intervention group, there might have been an additional “resource” limitations which is not presented, e.g. that a physical therapist would not be able to do more than a session every 4 hours or than four times a day. Would it be possible to elaborate on the available staff resources to deliver the intervention? If we assume that the lack of staff resources were an additional limitation not mentioned by the authors, it supports our belief that a successful early rehabilitation program has to be interprofessional, including both physical therapists and nursing staff to maximize physical rehabilitation opportunities throughout the day [5, 10].
Finally, the authors chose a primary outcome (Physical Component Summary Score of the SF-36 version 2) that does take into account mortality. Approximately one third of patients enrolled died before the functional outcome could be assessed. This functional outcome “truncated due to death” creates challenges in the definition and statistical evaluation of the treatment effect, and deserves careful planning of statistical analyses [11].
An additional 25% of enrolled patients were lost to follow-up. Therefore 57% of the enrolled patients did not contribute to the primary outcome measure, making the overall results of the study difficult to interpret.
In summary, we think that the conclusion and key message do not entirely reflect the study results. Physical therapy interventions of 90 min vs. 30 minutes were not achieved in the study. Additionally, less than half of enrolled patients contributed data to the primary outcome measure and excluding patients who did not survive limits the interpretation of this complex intervention.
References
1. Wright, S.E., et al., Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial. Thorax, 2017.
2. Connolly B and Denehy L Hindsight and moving the needle forwards on rehabilitation trial design. Thorax. 2018 Mar;73(3):203-205. doi: 10.1136/thoraxjnl-2017-210588. Epub 2017 Nov 14. http://thorax.bmj.com/content/73/3/203
3. Fuest, K. and S.J. Schaller, Recent evidence on early mobilization in critical-Ill patients. Curr Opin Anaesthesiol, 2018.
4. Schweickert, W.D., et al., Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet, 2009. 373(9678): p. 1874-82.
5. Schaller, S.J., et al., Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet, 2016. 388(10052): p. 1377-1388.
6. Investigators, T.S., et al., Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study. Crit Care, 2015. 19: p. 81.
7. Moss, M., et al., A Randomized Trial of an Intensive Physical Therapy Program for Patients with Acute Respiratory Failure. Am J Respir Crit Care Med, 2016. 193(10): p. 1101-10.
8. Bein, T., et al., S2e guideline: positioning and early mobilisation in prophylaxis or therapy of pulmonary disorders : Revision 2015: S2e guideline of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI). Anaesthesist, 2015. 64 Suppl 1: p. 1-26.
9. Stephens, R.J., et al., Practice Patterns and Outcomes Associated With Early Sedation Depth in Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis. Crit Care Med, 2018. 46(3): p. 471-479.
10. McWilliams, D., et al., Earlier and enhanced rehabilitation of mechanically ventilated patients in critical care: A feasibility randomised controlled trial. J Crit Care, 2018. 44: p. 407-412.
11. Colantuoni, E., et al., Statistical methods to compare functional outcomes in randomized controlled trials with high mortality. BMJ, 2018. 360: p. j5748.
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...
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 per day in a specific year or time period. Assuming that participants underestimate smoke intensity, it is likely that the association between smoke intensity and COPD is less strong than the association between smoke duration and COPD. This weaker association is then not due to the relative contribution of smoke intensity compared to that of duration, but to recall bias.
To conclude, the statements made in the paper seem to be very convincing, but are based on research with methodological limitations. Prospective studies assessing the relative contribution of smoke intensity and smoke duration are thus urgently needed.
1. Bhatt SP, Kim YI, Harrington KF, Hokanson JE, Lutz SM, Cho MH, et al. Smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years. Thorax. 2018.
2. Marks GB. Guiding policy to reduce the burden of COPD: the role of epidemiological research. Thorax. 2018.
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...
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 patient is exposed to macrolides and explains the recommendation of discontinuing long term macrolide use prior to resampling for M. abscessus abscessus. Furthermore, the use of macrolides for the treatment of other Mycobacterial species (for example M. fortuitum or M. smegmatis) that possess functional erm genes is not recommended. 5 Thus when declaring someone to have cleared M. abscessus when on treatment, can one really be sure that this is not simply an assumption of quiescent state to later rear its’ ugly head? Likewise the declaration of a re-emergence on cessation of treatment may be the head rearing.
Much of the experience of macrolide use appears historical dating back to the mid 1990s, and their apparent efficacy reflects pre-subspeciating taxonomy where strains may have been identified as M. abscessus but in actual fact could have been M. abscessus massiliense with dysfunctional erm(41) genes and therefore macrolide sensitivity. 2
Although we welcome a guideline to direct clinical practice, we note that there has been little progress in updating the evidence and this most recent guideline is based on treatment protocols devised almost 25 years ago which do not reflect advances in bacterial taxonomy and genetic analysis of antimicrobial resistance. Work to delineate optimal therapy for M. abscessus complex infections is urgently warranted.
Ref.
1. Haworth et al. (2017). Thorax 72: Suppl 2
2. Bastian et al. (2011). Anti Agen & Chemo 55: 775-781
3. Carryn et al. (2003). Infect. Dis. Clin. N. Am 17: 615-634
4. Medjahed et al. (2010). Trend Micro 18: 117-123
5. Nagh et al. (2005). JAC 55: 170-177
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
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...
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 a corrected standard error. Some included studies provided appropriate data to calculate this (standard error of the differences), or a corrected standard error can be imputed using “borrowed” correlation co-efficients from other studies.
In our Cochrane Review we used the former method (2). In response to the feedback provided by Ekström et al, we conducted a sensitivity analysis with an alternative meta-analysis (accounting for use of cross over data) using correlation co-efficients and corrected standard errors. The data are presented using standardised mean differences. The results demonstrate a change from baseline SMD -0.14 (95% CI -0.40 to 0.13) and a post treatment score SMD -0.55 (95% CI -0.76 to -0.35) (Figure 1, https://doi.org/10.6084/m9.figshare.5743137). This is similar to our original published results which found a change from baseline score SMD -0.09 (95% CI -0.36 to 0.19) and a post treatment score SMD -0.28 (95% CI -0.5 to -0.05). Both analyses draw the same conclusion that there is a significant but small effect size for the use of opioids for breathlessness.
Ekström et al raise concerns regarding the use of a fixed effects versus a random effects model (1). Based on the assumption that studies would have a small sample size we chose a priori to use a fixed effects model. As Higgins and Green describe: a random effects model will award relatively more weight to smaller studies because smaller studies are more informative for learning about the distribution of the effects across studies than for learning about an assumed common intervention effect (3). Therefore, if a random effects model is inappropriately applied, in particular, if the results of small studies are systematically different to the results of larger ones, the random effects model can inappropriately exacerbate the effects of any bias (4).
The choice and rationale for a fixed effects model was outlined in advance in our protocol. This protocol was peer reviewed prior to publication (2). Consistent with Higgins and Green, we presented both a fixed effects and random effects model in the sensitivity analysis, and found no differences in effect (3). Following additional sensitivity analysis as described above, there remains very little difference between the fixed effects model in the change from baseline scores (SMD -0.14 (95% CI -0.40 to 0.13)) and the random effects model (SMD -0.21 (95% CI -0.55 to 0.12)), and in the post treatment score fixed effects model (SMD -0.55 (95% CI -0.76 to -0.35)) and random effects model (SMD -0.69 (95% CI -1.08 to -0.29)).
A second limitation from the opioids for breathlessness data is the use of different scales to measure the same outcome (e.g. visual analogue scale (VAS) or Borg scale), with scales measured on different lengths, with different extremes, and different gradations of intensity. In order to combine data on different scales, standardised mean differences are required, which are calculated by dividing the mean difference by a pooled estimate of the between-patient standard deviation. However, combining this between-patient standard deviation with the within patient variation imputed from the corrected standard error described as above to incorporate crossover trials is not always possible from the available data. It is difficult to interpret the resulting standardised mean differences from cross-over trials.
Transforming the data as described above works if the data are reported as either change from baseline or post treatment scores, however it is unclear if it is also appropriate to combine them in a single meta-analysis, and to combine them in a single meta-analysis using standardised mean difference (SMD). Higgins and Green state that post treatment scores can be combined with change from baseline scores when using an unstandardised mean difference, however, they should not be combined as a standardised mean difference using the standard deviation of the change scores (as these are not the same units as the standard deviation of the final scores) (3). Therefore, it makes it difficult to combine data from different scales as outlined above, as well as combining post treatment and change from baseline scores in one single meta-analysis. Originally, we separated post treatment and change from baseline scores. In a further subsequent sensitivity analyses performed in response to the feedback, we combined these but separated by scale, see Figure 2 (https://doi.org/10.6084/m9.figshare.5743134.v2).
Ekström et al discussed at length the primary outcome of breathlessness, but they did not take into account adverse events or multidimensional assessment of the use of opioids (1). We noted increased adverse events including drowsiness, nausea, and constipation, as well as a significant difference in the mastery domain scores in one included trial, suggesting that participants may feel less in control when using morphine. We believe it is important to consider the evidence in its entirety, rather than focusing on only one effect size score.
Ekström et al have suggested that we downgraded the quality of evidence based on concerns about study size alone (1). We used GRADE methodology to rate the quality of the evidence and our decision to downgrade the quality of the evidence was based on the fact that more than 50% of included trials did not report on allocation concealment, blinding of participants or personnel, or blinding of outcome assessment. This is potentially a serious limitation when the primary outcome (i.e. change in breathlessness) is entirely subjective. We acknowledge that study size per se does not influence the internal validity of trial results and that some of the trials included in the review were designed with sufficient statistical power.
The ‘size bias’ criterion was suggested by the Cochrane editorial team during the review process of our manuscript, as there is empiric evidence that study size may be a surrogate marker of trial quality when the reporting on aspects of trial quality is poor (4). In other fields, small study effects have been shown to distort the results of meta-analyses (5). Many of the papers included in the review did not provide sufficient information to adequately assess trial quality, and because all the studies included were small in relative terms (with less than 50 participants per trial) we believe that it is important to highlight that the quantitative data synthesis was based on the pooling of relatively small studies.
We included the study by Woodcock 1982, but this is more correctly referenced in our review as Bar-Or 1982 (6). We included the study by Johnson et al (2002) in the review, but excluded it from the meta-analyses as the data was not normally distributed and medians and interquartile ranges cannot be imputed into a meta-analysis, consistent with the Cochrane Handbook (3, 7). Although Ekström et al commented that study selection should align to predefined eligibility criteria with reasons for exclusion stated to minimise selection bias, our studies were selected according to a published protocol with study types, inclusion and exclusion criteria specified (1).
While we value the opinion provided by Ekström et al, the additional sensitivity analyses reported here do not change our review conclusions (1,2). There is some small, low quality evidence that shows benefit for the use of parental or oral opioids to palliate breathlessness in the short term. The magnitude of this benefit is at best modest and given the potential adverse events and the lack of any evidence suggesting an improvement in overall quality of life, longer-term studies with multi-dimensional scales are required to ascertain whether any benefits outweigh the potential long-term risks, particularly where opioids are being used in those with chronic stable disease in the outpatient setting (8).
Acknowledgements
We thank Christopher Cates for his extensive input on this sensitivity analysis and comments on this letter, Kerry Dwan, Toby Lasserson and the Statistical Methods Group, and Julian Higgins for his report on the interpretation of this data.
References:
1. Ekström M, Bajwah S, Bland JM, Currow D, Hussain J, Johnson M. One evidence base; three stories: do opioids relieve chronic breathlessness? Thorax 2017
2. Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database of Systematic Reviews 2016, Issue 3. Art. No.: CD011008. DOI: 10.1002/14651858.CD011008.pub2.
3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
4. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982-9.
5. Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, et al. Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. BMJ 2010;341:c3515.
6. Bar-Or D, Marx JA, Good J. Breathlessness, alcohol and opiates. The New England Journal of Medicine 1982;306(22):1363–4.
7. Johnson MJ, McDonagh TA, Harkness A, McKayd SE, Dargie HJ. Morphine for the relief of breathlessness in patients with chronic heart failure--a pilot study. European Journal of Heart Failure 2002;4(6):753–6.
Figure 1: https://doi.org/10.6084/m9.figshare.5743137 Meta-analysis – Opioids for palliation of breathlessness conducted using alternative methods for use of crossover data with results separated according to post treatment scores and change from baseline scores.
Figure 2: https://doi.org/10.6084/m9.figshare.5743134.v2 Meta-analysis – Opioids for the palliation of breathlessness using alternative method for use of crossover data, combining post treatment and change from baseline scores but separating by scale used to measure breathlessness.
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...
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 initiative, led by the Chief Scientific Officer of the Department of Health to address training and education in healthcare science. This drew on stakeholder consultation in 2008 with policy proposals published in 2010. A central component of this initiative is a three year, part time Master of Science degree aimed at equipping future scientist leaders. The students involved include NHS employed Medical Physicists, Cardiologists, Vascular, Gastrointestinal and Respiratory Physiologists. These capacities are all relevant to Respiratory medicine and an integrated future training of Specialist trainee Physicians with scientists.
It is noteworthy, and a concern, that Cardiology trainee scientists have consistently outnumbered Respiratory trainees in the NHS scientist masters course (c.3:1). There are a number of potential explanations for this but we feel it is possible that some respiratory centres do not know of the program and the potential for fully funded trainee places. Funding is available covering both the MSc course and the salary of the scientists. This is made available following the provision of a business case made by individual departments and funds currently derive from demarcated regional education budgets and not the host Department or hospital. We feel this represents an important opportunity for capacity building for respiratory medicine, and the discussion raised in Dr Phillips editorial, indicating that internship in a respiratory lab led to better respiratory training for clinicians.
Precision, personalised medicine is exemplified by recent breakthroughs in Respiratory Medicine. These include the use of small molecule modulators of the Cystic Fibrosis Transmembrane Regulator (CFTR) channel in patients with Cystic Fibrosis lung disease. Future research of such approaches and measuring the efficacy of potentially transformational treatments in Respiratory Medicine is dependent on the capacity for U.K respiratory physiology and training for both clinicians and scientists. We feel that the current 4–5 year window to address respiratory physiology training for specialist training of Physicians highlighted by Dr Phillips is an opportunity for further coordination involving both Physicians and physiological scientists. The faculty developed for the training of NHS respiratory scientists in Newcastle would be very keen to pursue this with all respiratory colleagues.
.
Yours sincerely
Chris Ward, Ian Forrest, Graham Burns
References:
1. How do we improve training in pulmonary physiology and the interpretation of lung function tests? Phillips G. Thorax. 2018 Jan;73(1):2-3. doi: 10.1136/thoraxjnl-2017-210140. Epub 2017 Oct 17.
2. Does training respiratory physicians in clinical respiratory physiology and interpretation of pulmonary function tests improve core knowledge? M Patout, L Sesé, T Gille, B Coiffard, S Korzeniewski, E Lhuillier, A Pradel, C Tardif, A Chambellan, C Straus, S Matecki, T Perez, L Thiberville, A Didier. Thorax. 2018 Jan;73(1):78-81. doi: 10.1136/thoraxjnl-2016-209136. Epub 2017 Mar 3.
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
Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Although inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivatio...
Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Although inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivation of smoking cessation, such as lower nicotine dependency4, older age,4 5 6 higher socioeconomic group,5 being married,5 and higher education.7 Therefore, the integrated smoking cessation interventions should be considered besides CT lung screening.
In summary, the study performed by Kate Brain and colleagues provides important new data regarding the effect of CT lung cancer screening for high-risk smokers. It also sheds light on the issue that smoking cessation needs multi-disciplinary counseling in combination with pharmacotherapy8. Here, we would like to emphasize that the impact of lung CT screening on the motivation of active smokers is a double-edged sword. The positive CT scan results could bring a higher motivation of smoking cessation, whereas the negative and the indeterminate results might actually decrease the motivation, or even let smokers give up the smoking cessation. For high-risk active smokers without positive CT screening results, specific medical consultation and more support are needed as soon as possible.
A quit rate of 21% in controls and 24% in screened persons show that CT screening is a poor motivation to quit. The authors emphasize that the quit rate was 30% in patients with a positive result on CT who needed additional clinical investigation, however, the quit rate was only 15% in persons receiving a negative CT result. This shows that CT screening lowers the motivation to quit if a negative result (expected for the majority) nourishes misperceptions. Zeliadt et al. ( JAMA Intern Med 2015; 175:1530-7) found that in 49% these beliefs were reinforced and potentially exacerbated by screening and lowered the motivation to participate in smoking cessation programs. Therefore CT screening for lung cancer without accompanying smoking cessation program could be harmful.
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).
Show MoreIn areas where the majority of active cases are amongst those...
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.
Show MoreThe 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...
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...
Show MoreSir
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...
Show MoreWhile 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
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...
Show MoreWe 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...
Show MoreAMENDED
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
Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Show MoreAlthough inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivatio...
A quit rate of 21% in controls and 24% in screened persons show that CT screening is a poor motivation to quit. The authors emphasize that the quit rate was 30% in patients with a positive result on CT who needed additional clinical investigation, however, the quit rate was only 15% in persons receiving a negative CT result. This shows that CT screening lowers the motivation to quit if a negative result (expected for the majority) nourishes misperceptions. Zeliadt et al. ( JAMA Intern Med 2015; 175:1530-7) found that in 49% these beliefs were reinforced and potentially exacerbated by screening and lowered the motivation to participate in smoking cessation programs. Therefore CT screening for lung cancer without accompanying smoking cessation program could be harmful.
Pages