The National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrain...
The National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrained. Therefore, it is vital that a pragmatic approach is taken to prioritise the most cost-effective, evidence-based strategies for identifying people most at risk of latent TB infection and progression to active TB disease. Cavany et al’s excellent paper raises certain key points relating to the wider policy implications of the cost-effectiveness of TB prevention strategies in low-burden settings.
First, as set out in the World Health Organization’s “End TB Strategy”(4) and PHE and NHS England’s “Collaborative Tuberculosis Strategy 2015-2020”,(5) the shared aim of the global TB community is to eliminate tuberculosis (defined as less than one case of active TB disease per 100,000 population). This goal is especially pertinent with regards to cost-effectiveness in low burden settings like Western Europe because, as incidence and prevalence of TB continue to decline, the cost per tracing episode will increase, probably non-linearly, and therefore meeting cost-effectiveness thresholds will become increasingly difficult.(6) For example, in North West England, declines in TB incidence have been associated with an increase in the proportion of TB cases who have complex social and clinical risk factors requiring enhanced case management (ECM) and hence greater per patient resource allocation.(7)
Second, cost-effectiveness estimates often assume homogeneity of clinical and social risk factors of TB patients and contacts when, in practice, such populations are profoundly diverse. We conducted an analysis of our North West England cohort of 2,139 TB cases and their 10,019 contacts. Our research showed that prevalence of active TB disease among contacts of patients with ETB was similar to the London cohort (0.44% versus 0.7% in Cavany et al, respectively) but varies widely according to the index patient’s social and clinical complexity as measured by ECM need.(1) Excluding contacts who would meet other criteria for routine contact tracing and/or active case finding (e.g. migrants, homeless people, or drug users), the rate of active TB disease in contacts of extrapulmonary TB patients with no ECM need versus the highest ECM need were 0.06% versus 1.5%, respectively.(8) Therefore, whilst we agree that contact tracing of all ETB contacts may not be cost-effective, focusing on a small number of high-risk ETB contacts (in whom approximately 1 in 66 will have active TB disease in our North West cohort) may still be an appropriate allocation of resources in the context of aiming towards regional elimination of TB.
Third, robust cost-effectiveness analyses such as Cavany et al’s should motivate the TB community in England to evaluate the predominant drivers of the costs of their TB detection and prevention services. If existing contact tracing strategies are, as in Cavany et al’s research, shown to lack cost-effectiveness, TB multi-disciplinary teams and service providers should consider designing and implementing innovative approaches that are more efficient and better value for money. Identification and characterisation of patients’ risk of an adverse treatment outcome and contacts’ risk of a positive screening event using ECM is one simple strategy,(7,8) but there are many other potential options including: electronic or virtual screening; community engagement and outreach clinics; patient and peer-led active case finding; and socioeconomic support, incentives and enablers. It is essential that future research designing and implementing such novel strategies follows Cavany et al’s lead and includes rigorous cost-effectiveness analysis in order to best inform and guide policy makers and public health commissioners.(9)
Cavany et al’s research highlights the importance of high-quality cost-effectiveness analysis to guide TB policy. In order to provide optimal TB detection, prevention, and care services tailored to individuals, especially those in underserved groups, future TB policy decisions should take into account heterogeneity within TB populations and the inevitable decrease in cost-effectiveness of interventions in line with declining TB rates. Without such considerations, we will be unlikely to meet the goal of eliminating TB in England.
References
1) Wingfield T, MacPherson P, Cleary P, Ormerod LP. High prevalence of TB disease in contacts of adults with extrapulmonary TB. Thorax. 2018 Aug;73(8):785-787. doi: 10.1136/thoraxjnl-2017-210202. Epub 2017 Nov 16.
2) Cavany SM, Sumner T, Vynnycky E, Flach C, White RG, Thomas HL, Maguire H, Anderson C. An evaluation of tuberculosis contact investigations against national standards. Thorax. 2017 Aug;72(8):736-745. doi: 10.1136/thoraxjnl-2016-209677. Epub 2017 Apr 7.
3) McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics. 2008;26(9):733-44.
6) Smit GS, Apers L, Arrazola de Onate W, Beutels P, Dorny P, Forier AM, Janssens K, Macq J, Mak R, Schol S, Wildemeersch D, Speybroeck N, Devleesschauwer B. Cost-effectiveness of screening for active cases of tuberculosis in Flanders, Belgium. Bull World Health Organ. 2017 Jan 1;95(1):27-35. doi: 10.2471/BLT.16.169383. Epub 2016 Nov 3.
7) Tucker A, Mithoo J, Cleary P, Woodhead M, MacPherson P, Wingfield T, Davies S, Wake C, McMaster P, Bertel Squire S. Quantifying the need for enhanced case management for TB patients as part of TB cohort audit in the North West of England: a descriptive study. BMC Public Health. 2017 Nov 15;17(1):881. doi: 10.1186/s12889-017-4892-5.
8) Wingfield T, MacPherson P, Sodha P, Tucker A, Mithoo J, Squire S B, Cleary P. The association of TB patients’ social risk factors and ethnicity with prevalence of TB infection and disease among their contacts: a cohort study in North West England. Under review with International Journal of Tuberculosis and Lung Disease, August 2018.
9) Lönnroth K, Migliori GB, Abubakar I, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015 Apr;45(4):928-52. doi: 10.1183/09031936.00214014
The global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Many respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patie...
The global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Many respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patients-tourists to remain in a travel destination one month more than scheduled, launches their cost of stay and many times they are proven unable to follow this recommendation.
In our opinion, one size does not fit all. The 4-week period seems too long for a patient with pulmonary embolism severity index I or II, no evidence of right ventricular dysfunction on an imaging test, negative laboratory biomarkers on presentation (low risk patient) and a normal PaO2 on room air (4). On the other hand, the 4-week period and even more the 5-day period may be too short for a patient with pulmonary embolism severity index III-V, evidence of right ventricular dysfunction on an imaging test and positive laboratory biomarkers on presentation (intermediate high risk patient), who has a significantly higher mortality rate during the first thirty days even without traveling (4).
Thus, we believe that the risk of flying after being diagnosed with pulmonary embolism is not the same for all patients and in every case we should take into consideration the risk stratification on presentation and the PaO2 level. Further carefully designed studies taking into account risk stratification will give the answer to the tough question “should I stay or should I go” after pulmonary embolism.
References
The World Bank. Air transport, passengers carried. https://data.worldbank.org/indicator/IS.AIR.PSGR Date last accessed: December 7, 2018.
International Air Transport Association. Medical manual 11th edition. https://www.iata.org/publications/Documents/medical-manual.pdf 2018
Ahmedzai S1, Balfour-Lynn IM, Bewick T, Buchdahl R, Coker RK, Cummin AR, Gradwell DP, Howard L, Innes JA, Johnson AO, Lim E, Lim WS, McKinlay KP, Partridge MR, Popplestone M, Pozniak A, Robson A, Shovlin CL, Shrikrishna D, Simonds A, Tait P, Thomas M; British Thoracic Society Standards of Care Committee. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax. 2011 Sep;66 Suppl 1:i1-30.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k.
We read with interest the findings of Miele et al. on the relationship between environmental exposures and decline in lung function (1). The authors reported that living in urban settings and living at high altitude were associated with accelerated decline in pre-bronchodilator FEV1 and FVC. Investigating the effects at area level is important from a public health perspective and extra analysis on this valuable dataset as suggested below will help to untangle these links further.
Study participants were recruited from four settings in Peru: Lima, Tumbles, urban Puno and rural Puno (1). Urban living and high-altitude dwelling (as binary variables) were defined based on these four settings. The authors compared the effect of urban living (Lima and urban Puno) with rural living (Tumbes and rural Puno); and the effect of high-altitude dwelling (urban Puno and rural Puno) with low-altitude dwelling (Lima and Tumbes). It is possible that the observed independent effects found by the authors of urban living and high-altitude dwelling may be driven by the urban Puno group (high altitude and urban living). In other words, there may be an interaction between urban living and high-altitude dwelling and investigating this potential interaction would be informative.
As discussed by the authors, the adverse effect of high-altitude dwelling on lung function decline may partly be related to hypoxia and adverse effects from living in urban settings may be related to outdoor air...
We read with interest the findings of Miele et al. on the relationship between environmental exposures and decline in lung function (1). The authors reported that living in urban settings and living at high altitude were associated with accelerated decline in pre-bronchodilator FEV1 and FVC. Investigating the effects at area level is important from a public health perspective and extra analysis on this valuable dataset as suggested below will help to untangle these links further.
Study participants were recruited from four settings in Peru: Lima, Tumbles, urban Puno and rural Puno (1). Urban living and high-altitude dwelling (as binary variables) were defined based on these four settings. The authors compared the effect of urban living (Lima and urban Puno) with rural living (Tumbes and rural Puno); and the effect of high-altitude dwelling (urban Puno and rural Puno) with low-altitude dwelling (Lima and Tumbes). It is possible that the observed independent effects found by the authors of urban living and high-altitude dwelling may be driven by the urban Puno group (high altitude and urban living). In other words, there may be an interaction between urban living and high-altitude dwelling and investigating this potential interaction would be informative.
As discussed by the authors, the adverse effect of high-altitude dwelling on lung function decline may partly be related to hypoxia and adverse effects from living in urban settings may be related to outdoor air pollution and comorbid conditions (2, 3). Investigating interaction between high-altitude dwelling and urban living may help tease out the underlying drivers of accelerated lung function decline. It is also critical to understand what factors in these areas mediate the adverse impact on lung function decline and the data could be further analysed to investigate potential mediators. These analyses are the first step to translation of this evidence to public health measures.
We additionally note that the high-altitude dwelling group had higher prevalence of COPD at baseline (Table 1) and it appeared that COPD was not adjusted for in the final model (Table 3) (1). If this is the case, the inbalance of COPD may have confounded the association between high-altitude dwelling and lung function decline. We have shown that lung function trajectories leading to COPD often exceed the normal rate of decline (4). Therefore, it is also highly likely that, in this analysis, lung function decline may vary between those who have COPD and those who do not, which warrants an interaction analysis.
Understanding the adverse effect of residential place (i.e. urban and high-altitude dwelling) on lung function decline would have significant public health implications. Further research is needed to tease out the important drivers of these observed effects.
References
1. Miele CH, Grigsby MR, Siddharthan T, Gilman RH, Miranda JJ, Bernabe-Ortiz A, Wise RA, Checkley W. Environmental exposures and systemic hypertension are risk factors for decline in lung function. Thorax 2018.
2. Rice MB, Ljungman PL, Wilker EH, Dorans KS, Gold DR, Schwartz J, Koutrakis P, Washko GR, O'Connor GT, Mittleman MA. Long-term exposure to traffic emissions and fine particulate matter and lung function decline in the Framingham heart study. Am J Respir Crit Care Med 2015; 191: 656-664.
3. Schikowski T, Schaffner E, Meier F, Phuleria HC, Vierkotter A, Schindler C, Kriemler S, Zemp E, Kramer U, Bridevaux PO, Rochat T, Schwartz J, Kunzli N, Probst-Hensch N. Improved air quality and attenuated lung function decline: modification by obesity in the SAPALDIA cohort. Environmental health perspectives 2013; 121: 1034-1039.
4. Bui DS, Lodge CJ, Burgess JA, Lowe AJ, Perret J, Bui MQ, Bowatte G, Gurrin L, Johns DP, Thompson BR, Hamilton GS, Frith PA, James AL, Thomas PS, Jarvis D, Svanes C, Russell M, Morrison SC, Feather I, Allen KJ, Wood-Baker R, Hopper J, Giles GG, Abramson MJ, Walters EH, Matheson MC, Dharmage SC. Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. Lancet Respir Med 2018.
According to recent study published by Sebastian et al., (1) electronic cigarette vapor impairs the activity of alveolar macrophages, which engulf and remove dust particles, bacteria, and allergens that have evaded the other mechanical defenses of the respiratory tract. This study finding is important and it shows that the long term health impact of e-cigarettes use may be more harmful than we know (2).
Meanwhile, industry, tobacco research community and the online information are promoting electronic cigarette as a less harmful tobacco cessation tool. However, before more leeway to advertise the harm-reduction benefits of vaping products, we believe that the first step would be to establish whether vaping products are indeed safer tobacco cessation device or harm reduction tool (3). Moreover, currently available evidence (including clinical guidelines and position statements of credible medical organizations) based information need to ensure that people are protected from commercial interests and are able to make informed decisions based on current best evidence on electronic cigarette and its long term health effects (3). It is our moral obligation that we should not be promoted electronic cigarette to our children and people those who never wanted to smoke tobacco. At the same time, it is important to promote the proven non-tobacco nicotine products such as Nicotine Replacement Therapy (gum or inhalators) to smokers those who are sincerely wanted to quit.
According to recent study published by Sebastian et al., (1) electronic cigarette vapor impairs the activity of alveolar macrophages, which engulf and remove dust particles, bacteria, and allergens that have evaded the other mechanical defenses of the respiratory tract. This study finding is important and it shows that the long term health impact of e-cigarettes use may be more harmful than we know (2).
Meanwhile, industry, tobacco research community and the online information are promoting electronic cigarette as a less harmful tobacco cessation tool. However, before more leeway to advertise the harm-reduction benefits of vaping products, we believe that the first step would be to establish whether vaping products are indeed safer tobacco cessation device or harm reduction tool (3). Moreover, currently available evidence (including clinical guidelines and position statements of credible medical organizations) based information need to ensure that people are protected from commercial interests and are able to make informed decisions based on current best evidence on electronic cigarette and its long term health effects (3). It is our moral obligation that we should not be promoted electronic cigarette to our children and people those who never wanted to smoke tobacco. At the same time, it is important to promote the proven non-tobacco nicotine products such as Nicotine Replacement Therapy (gum or inhalators) to smokers those who are sincerely wanted to quit.
A new congressionally mandated National Academies of Sciences, Engineering and Medicines’ (NASEM) comprehensive review of more than 800 peer reviewed scientific studies on health effects of vaping on adolescents concluded that “There is moderate evidence for increased cough and wheeze in adolescents who use electronic-cigarettes, and an increase in asthma exacerbations” (4).
The harms that e-cigarettes currently pose to non-smoking teens and young adults (those who never wanted to smoke) far outweigh the potential benefits (5).Therefore, the NASEM (5) recommendations and emerging research on electronic cigarette use and potential long term harm (1) should be appropriately reflect in the future clinical guidelines and position statements of credible medical organizations.
REFERENCES:
(1). Scott A, Lugg ST, Aldridge K, Lewis KE, Bowden A, Mahida RY, Grudzinska FS, Dosanjh D, Parekh D, Foronjy R, Sapey E, Naidu B, Thickett DR. Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages. Thorax. 2018 Aug 13. pii: thoraxjnl-2018-211663. doi: 10.1136/thoraxjnl-2018-211663.
(2). Huang SJ, Xu YM, Lau ATY. Electronic cigarette: A recent update of its toxic effects on humans. J Cell Physiol. 2018 Jun;233(6):4466-4478. doi: 10.1002/jcp.26352
(3). Bandara AN, Mehrnoush V. Electronic cigarettes: adolescent health and wellbeing. Lancet. 2018; 11;392(10146):473. doi: 10.1016/S0140-6736(18)31177-2.
(4). National Academies of Sciences and Engineering and Medicine. Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public health consequences of e-cigarettes. The National Academies Press, Washington, DC; 2018. Available at: https://www.nap.edu/catalog/24952/public-health-consequences-of-e-cigare...
(5). Soneji S, Sung HY, Primack BA, Pierce JP, Sargent JD. "Quantifying population-level health benefits and harms of e-cigarette use in the United States" PLOS ONE 2018; DOI: 10.1371/journal.pone.0193328.
Although electronic cigarettes (ECs) are a much less harmful alternative to tobacco cigarettes, there is concern as to whether long-term ECs use may cause risks to human health. There are reasonable concerns and should be elucidated as soon as possible to learn how to best employ these products, causing the least possible damage to users.
Scott and colleagues aimed at define whether e-cig vapors have a negative impact on human alveolar macrophages (AMs) viability and function (1). They tested human AMs from lung resection specimens from healthy donors by exposing these cells to the electronic cigarette vapour condensate (ECVC).
First of all, the authors dedicated a detailed explanation to the method used to condensate the vapour, but the protocol used to generate vapour is quite ambiguous, omitting to indicate puff volume, puff number, and in particular if the pump used to aspirate the vapors were able to generate the correct puff profile (2). This is a crucial step in the validation process of an exposure method, because if the vapours are generated with incorrect regimes, they can lead to the production of inaccurate ECVC and thus to distorted results invalidating all the conclusions of the study. We think the author could detail the regimen employed for vapour generation.
Furthermore, airway macrophages are resident in the connective tissue and not exposed directly to the liquid-air interface, therefore the method used for the exposition of these cells...
Although electronic cigarettes (ECs) are a much less harmful alternative to tobacco cigarettes, there is concern as to whether long-term ECs use may cause risks to human health. There are reasonable concerns and should be elucidated as soon as possible to learn how to best employ these products, causing the least possible damage to users.
Scott and colleagues aimed at define whether e-cig vapors have a negative impact on human alveolar macrophages (AMs) viability and function (1). They tested human AMs from lung resection specimens from healthy donors by exposing these cells to the electronic cigarette vapour condensate (ECVC).
First of all, the authors dedicated a detailed explanation to the method used to condensate the vapour, but the protocol used to generate vapour is quite ambiguous, omitting to indicate puff volume, puff number, and in particular if the pump used to aspirate the vapors were able to generate the correct puff profile (2). This is a crucial step in the validation process of an exposure method, because if the vapours are generated with incorrect regimes, they can lead to the production of inaccurate ECVC and thus to distorted results invalidating all the conclusions of the study. We think the author could detail the regimen employed for vapour generation.
Furthermore, airway macrophages are resident in the connective tissue and not exposed directly to the liquid-air interface, therefore the method used for the exposition of these cells to ECVC is definitely incorrect. It is important to consider that substances in the ECVC must overcome the physiological barrier of the airway epithelium, before getting to reach the macrophages. The airway epithelium forms the first continuous line of defense, able to dynamically regulate its response to experienced luminal stimuli, against inhaled environmental insults, including chemicals (3). So, chemicals that will eventually come into contact with alveolar macrophages, will be just a fraction of those contained in ECVC. The method employed by authors could be applicable to airway epithelial cells, but not to macrophages.
All of this makes it difficult to translate the results obtained by Scott and colleagues in the real exposure of these cells to the vapours.
Additionally, the exposition of AMs to ECVC for 24 hours continuously is very far from the reality of using e-cig, generating an acute overexposure of cells to the effect of ECVC (that already in real life does not occur at all).
These observations could justify the differences of results obtained by Scott et al. in vitro, compared to those obtained in real-life in a cohort of long-term daily e-cigarette users (>3.5 years) who have never smoked in their life showing no warning of emerging lung injury as reflected in physiologic, clinical, radiologic, and inflammatory measures (4).
Finally, in consideration of the evidences emerging from real-life surveys and clinical studies of patients with respiratory conditions, supporting respiratory health benefits with e-cigarette use (5-7), it would be interesting to evaluate the effect of vapors in AMs from smokers and patients with COPD.
References
1. Scott A, Lugg ST, Aldridge K, et al. Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages.Thorax Published Online First: 13 August 2018. doi: 10.1136/thoraxjnl-2018-211663
2. Cunningham A, Slayford S, Vas C, Gee J, Costigan S, Prasad K. Development, validation and application of a device to measure e-cigarette users' puffing topography. Sci Rep. 2016 Oct 10;6:35071. doi: 10.1038/srep35071. PubMed PMID:27721496; PubMed Central PMCID: PMC5056340.
3. Brune, K., Frank, J., Schwingshackl, A., Finigan, J., and Sidhaye, V. K. (2015). Pulmonary epithelial barrier function: some new players and mechanisms. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L731–L745. doi: 10.1152/ajplung.00309.2014
4. Polosa, R., Cibella, F., Caponnetto, P., Maglia, M., Prosperini, U., Russo, C., et al. (2017). Health impact of E- cigarettes: a prospective 3.5-year study of regular daily users who have never smoked. Sci. Rep. 7:13825. doi: 10.1038/s41598-017-14043-2
5. Polosa, R., Morjaria, J., Caponnetto, P., Caruso, M., Strano, S., Battaglia, E., et al. (2014). Effect of smoking abstinence and reduction in asthmatic smokers switching to electronic cigarettes: evidence for harm reversal. Int. J. Environ. Res. Public Health 11, 4965–4977. doi: 10.3390/ijerph1105 04965
6. Polosa, R., Morjaria, J. B., Caponnetto, P., Caruso, M., Campagna, D., Amaradio,
M. D., et al. (2016). Persisting long term benefits of smoking abstinence and reduction in asthmatic smokers who have switched to electronic cigarettes. Discov. Med. 21, 99–108.
7. Polosa, R., Morjaria, J. B., Caponnetto, P., Prosperini, U., Russo, C., Pennisi, A., et al. (2016b). Evidence for harm reduction in COPD smokers who switch to electronic cigarettes. Respir. Res. 17:166. doi: 10.1186/s12931-016- 0481-x
We support the view of Drs. Polkey and Ambrosino that recommendations for clinical practice should not be based on either positive or negative preoccupation concerning the potential effectiveness of a treatment but rather on an impartial evaluation of the available data. In their editorial entitled ‘Inspiratory Muscle Training in COPD: can data finally beat emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1. It is unfortunate that they neglect a major part of available data, which could contribute to a more balanced and fair discussion about this intervention. We therefore deemed it necessary to add this missing evidence along with our own interpretation of recent findings to the discussion.
Complexity of studying add-on interventions to pulmonary rehabilitation
Based on the results from three recent multicentre trials2-4, Polkey and Ambrosino exclude a role for adjunctive IMT in the rehabilitation of patients with COPD. As emphasized in a previous opinion piece by Dr. Ambrosino5, it is important to distinguish between studies that evaluate the effects of inspiratory muscle training (IMT) as a standalone intervention (i.e. in comparison to no intervention or a sham control intervention) and studies on the effects of IMT added to a pulmonary rehabilitation program (PRP).
Concerning the first comparison, there is a large amount of data available s...
We support the view of Drs. Polkey and Ambrosino that recommendations for clinical practice should not be based on either positive or negative preoccupation concerning the potential effectiveness of a treatment but rather on an impartial evaluation of the available data. In their editorial entitled ‘Inspiratory Muscle Training in COPD: can data finally beat emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1. It is unfortunate that they neglect a major part of available data, which could contribute to a more balanced and fair discussion about this intervention. We therefore deemed it necessary to add this missing evidence along with our own interpretation of recent findings to the discussion.
Complexity of studying add-on interventions to pulmonary rehabilitation
Based on the results from three recent multicentre trials2-4, Polkey and Ambrosino exclude a role for adjunctive IMT in the rehabilitation of patients with COPD. As emphasized in a previous opinion piece by Dr. Ambrosino5, it is important to distinguish between studies that evaluate the effects of inspiratory muscle training (IMT) as a standalone intervention (i.e. in comparison to no intervention or a sham control intervention) and studies on the effects of IMT added to a pulmonary rehabilitation program (PRP).
Concerning the first comparison, there is a large amount of data available supporting the effectiveness of IMT in COPD. The most recent meta-analysis identified 43 randomized controlled trials6. Based on data from more than 1200 patients randomized to either IMT or control interventions authors concluded that IMT improved symptoms of dyspnea (Baseline Dyspnea Index), Quality of life (Saint George's Respiratory Questionnaire), functional capacity (Six minute walking distance, 6MWD) and maximal inspiratory pressure (PImax) in patients with COPD6. A clinically relevant difference of 43m (95%CI: 17m to 69m) in improvements in 6MWD after IMT in comparison to control was reported. The claim that ‘the appeal of IMT in COPD endures in the absence of data’ seems inappropriate in the light of above-mentioned findings. Polkey and Ambrosino further support their conclusions by mentioning that IMT also failed to improve exercise capacity in healthy subjects. They support this statement by citing a single study performed in 20017. In doing so they neglect results from a systematic literature review from 2012 including results from 46 randomized controlled studies. From the meta-analysis it was concluded that ‘respiratory muscle training improves endurance exercise performance in healthy individuals with greater improvements in less fit individuals and in sports of longer durations’8.
In contrast to studies of IMT as standalone intervention, when evaluating IMT as adjunctive intervention to PRP the evidence base looks different. In these type of studies, the control group already receives a very effective treatment (PRP) that will result in clinically relevant improvements in functional capacity and quality of life9. This makes it challenging to demonstrate additional effects of the adjunctive intervention on functional outcomes. Consequently, study designs are more complex, the database is less comprehensive and conclusions less straightforward6. IMT is not the only intervention that has failed to result in additional improvements in the 6MWD in this context (i.e. studying add-on interventions to PRP). A recent systematic review of RCTs studying the effects of various adjunctive interventions applied during PRP (including non-invasive ventilation, lower limb strength training, upper limb exercise training, oxygen supplementation, and inspiratory muscle training) did not observe additional effects of any of these adjunctive interventions during PR on the 6MWD10. When comparing the results of studies on the adjunctive effects of either lower limb strength training or IMT during PRP the results are of striking similarity. In both cases, the adjunctive interventions result in additional specific improvements in muscle function of the trained muscle groups without resulting in further improvements in 6MWD or quality of life measures10. It is questionable whether additional improvements in health related quality of life are a realistic goal when studying effects of these adjunctive interventions. Control groups participating in comprehensive PRP without adjunctive interventions will already achieve large and clinically relevant improvements in quality of life. It has further been demonstrated that changes in functional exercise capacity correlate poorly with changes in quality of life measures11. The questions should rather be whether in the specific case of IMT the adjunct intervention can (1) further reduce specific symptoms of exertional breathlessness and (2) whether it can optimize the response in functional capacity to PRP in participants who would otherwise achieve a less optimal response. In addition, the most appropriate candidates (i.e. likely responders to the adjunct intervention) and most suitable outcome measures still need to be identified. In order to find out whether the intervention can result in additional effects on functional capacity it will be necessary to strictly control both adherence with and quality of the adjunctive intervention as well as the symptom-based progression of the general exercise training program in this type of studies. To the best of our knowledge only one of the available studies has so far undertaken this effort4. The absence of evidence from studies on add-on interventions at this point should therefore not be interpreted as evidence of absence. Along these lines, the value of lower limb strength training during PRP in patients with COPD is currently not put into question based on limted available data. It is surprising however that, based on very similar data, it is concluded that there should be no role for IMT in the rehabilitation care of patients with COPD anymore. Instead of interpreting the results of recent studies2-4 as ultimate proof to discourage the use of IMT in COPD, we would rather argue that these findings should be used to optimize the design of future studies in this area. Unfortunately, Polkey and Ambrosino neglect most of the key findings from our recent trial that could be helpful for the design of these future studies. We will discuss these aspects in the final part of our comment. Prior to that we would like to review some of the other arguments that are used by Polkey and Ambrosino to support their statements.
IMT and the diaphragm in patients with COPD
They start by citing Leith and Bradleys pioneer work on ‘ventilatory muscle strength and endurance training’ from 1976. According to Polkey and Ambrosino these data, obtained in a handful of young healthy volunteers, support the assumption that inspiratory muscle training improves ‘test performance’ rather than ‘true contractility’12. We are unsure what their definition of ‘true contractility’ is, but it is generally accepted that the principles of specificity of resistance training apply to both training of the peripheral muscles13, and respiratory muscle training14. Results of several randomized controlled studies in patients with COPD have taught us that endurance type training (high flow, low resistance breathing) will specifically improve endurance capacity of the respiratory muscles, while PImax will only improve when subjects perform their breathing training against an external load of sufficiently large magnitude15. We would further like to comment on their statement that the reduction in inspiratory muscle strength in COPD is ‘due to hyperinflation rather than weakness’. While static hyperinflation certainly affects diaphragm contractility, several other etiological factors and biological mechanisms are known to contribute to respiratory muscle dysfunction in COPD16 17. These additional factors, many of which are also involved in peripheral muscle dysfunction, probably also help to explain the large variability in PImax that has been observed for a given level of static lung hyperinflation18.
It is also noteworthy that, while limitations in diaphragm contribution in patients are acknowledged on the one hand, diaphragm strength evaluated by phrenic nerve stimulation is subsequently put forward as the most relevant measure of changes in inspiratory muscle function in patients with COPD. This seems to be a limited approach especially for patients with COPD in whom, with increasing disease severity, the role of the rib cage muscles becomes more and more important19. As a consequence it seems reasonable that both specific tests of diaphragm strength as well as measures of global inspiratory muscle strength (and endurance) should be used to evaluate the effect of interventions on inspiratory muscle function20. The fact that IMT did not increase diaphragm strength as judged by isolated (artificial) phrenic nerve stimulation (Twitch-Pdi) is used as one of the arguments to support the conclusion that ‘the story of IMT defied data at each stage’. We would like to comment on this. Firstly, the paper that is cited in support of this observation demonstrates a poor relationship between changes in Twitch-Pdi and PImax 21. Secondly, the data, again obtained in a handful of healthy subjects, reveal a high variability between Twitch-Pdi measurements performed before and after an intervention period in a control group that did not perform IMT21. We therefore believe that conclusions with regard to these observations should be formulated more cautiously.
High fatigue resistance of the diaphragm is subsequently put forward as another argument why respiratory muscles of patients with COPD should not be trained. Indeed, adaptations in the diaphragm towards more fatigue resistance, most likely in response to chronic increased loading during resting breathing, are present in patients16 17. We also agree with Polkey and Ambrosino that it is unclear whether diaphragmatic muscle fatigue typically occurs during exercise breathing in patients with COPD. We would however like to highlight that acute length changes induced by exercise breathing (due to dynamic hyperinflation) will further impair the ability of the diaphragm to contribute to ventilation and will place increasing demands on accessory and rib cage muscles19. It is reasonable to assume that this breathing pattern would promote non-diaphragmatic respiratory muscle fatigue rather than diaphragm fatigue. Notwithstanding the difficulties in reliably assessing non-diaphragmatic muscle fatigue there are indications that fatigue in these muscles can develop selectively and separate from diaphragm fatigue, depending on the breathing pattern that is maintained22-24. The reluctance of Polkey and Ambrosino to acknowledge that the stimulus of exercise hyperpnea, as a consequence of further acute shortening of respiratory muscles and increased elastic loads due to dynamic hyperinflation, can result in acute disturbances in the load – capacity balance of the respiratory muscles of patients with COPD is surprising to say the least25 26. Especially given the fact that in an earlier opinion piece Dr Polkey highlighted the ‘specific relevance of [breathing close to] end inspiratory lung volume’ in patients with COPD, supported ‘by the observation that augmenting inspiratory muscle action at high lung volumes […] can extend exercise duration and increase peak work load27.’ It remains his secret as to why he would not appreciate a role for inspiratory muscle training in augmenting inspiratory muscle performance at high lung volumes during exercise breathing. In this context we would like to refer to a recent study28, in which we were able to demonstrate dyspnea relief during a constant work rate cycling test in response to IMT in patients with COPD. The effects of IMT were observed in patients with static and dynamic hyperinflation. Dyspnea reduction was observed in conjunction with a reduced activation of the diaphragm relative to maximum and in the absence of significant changes in ventilation, breathing pattern and operating lung volumes during cycling exercise 28. These data support previous findings of reduced diaphragm fatigability after IMT in patients with COPD29.
Choosing adequate outcomes to evaluate the effects of adjunctive IMT
As mentioned earlier it is a pity that some important results from our recent trial (IMT as adjunctive intervention during PRP)4, along with suggestions to improve the design of future studies have not been addressed by Polkey and Ambrosino. We would therefore like to highlight some of our key findings. In the absence of an additional effect of IMT on the 6MWD, we were able to demonstrate a significant improvement in the ability to sustain a submaximal effort during a constant work rate endurance-cycling test, as well as a reduction in symptoms of dyspnea at a standardized timepoint during this test4. The absence of evaluating symptoms at standardized levels of exertion has been identified as one of the shortcomings in one of the studies published earlier this year30. In our opinion these iso-time evaluations should be performed with the multidimensional dyspnea profile (MDP) in addition to Borg-CR 10 scale dyspnea scores in future studies. The higher sensitivity of submaximal constant work rate endurance exercise tests in comparison with the 6MWD has consistently been documented in pharmacological and non-pharmacological interventions in patients with COPD 31-33. The constant work rate endurance test therefore seems to be an optimal choice as a primary outcome for evaluating the effects of adjunctive interventions during PRP on functional capacity in future studies.
Optimization of patient selection
Furthermore, our recent findings also offer some food for thought with regard to selecting appropriate candidates for the adjunct intervention (IMT). While for peripheral muscle strength training it is reasonable to assume that the subjects with most pronounced weakness will benefit the most from the intervention, this might not be the case when selecting patients with respiratory muscle weakness. In our study we selected patients with pronounced weakness. This resulted in a sample of severely hyperinflated subjects (average RV >200%pred). The mechanical disadvantage of the respiratory muscles in these severely hyperinflated participants is probably a major contributor to the reduction in respiratory muscle pressure generating capacity. It has also been demonstrated that some of these severely hyperinflated patients are unable to dynamically hyperinflate during exercise34. These patients would consequently not undergo additional functional weakening of their inspiratory muscles due to further acute shortening during exercise. These patients will also not experience a great deal of additional loading on their respiratory muscles during exercise breathing due to both their inability to achieve major increases in tidal volume expansion, minute ventilation and their inability to dynamically hyperinflate during exercise breathing. Both factors (the large impact of mechanical disadvantage on weakness and the absence of acute disturbances in the load-capacity balance during exercise hyperpnoea) might render IMT less effective in these patients. Measurements of dynamic hyperinflation during exercise (which were not available in our study) would be needed to explore these issues further in order to identify participants who are potentially less likely to benefit from adjunctive IMT. In a further step one might choose to either exclude these patients from participation or to stratify randomization for this criterion.
Improving control of interventions
In addition, we were the first to show a relationship between quality and quantity of the performed IMT sessions and improvements in PImax4. We were able to control training parameters by using an electronic training device that stored training parameters recorded during home based IMT sessions35. We also observed that changes in PImax were significantly related to increases in the symptom-based progression of the intensity of the general exercise-training program and to improvements in functional exercise capacity4. This highlights the importance of monitoring and controlling both adherence to and quality of the adjunctive intervention, as well as the symptom based progression of the general exercise training components of the PRP in future studies. Sufficient time also needs to be allowed to establish the effects of IMT on symptom perception during exercise. This will enable patients to achieve larger increases in symptom based progression of the general exercise program. These increases in training intensity are a prerequisite to achieve additional benefits in functional capacity. Of the three studies of adjunctive IMT in COPD published this year2-4, ours was the only one that made an attempt to control for these parameters and we strongly encourage the use of these measures in future work in this area.
Conclusions
In summary, we feel that formulating strong statements to either discourage or recommend the use of IMT for patients with COPD in clinical practice is inappropriate at this stage. The results of recently published studies should in our opinion rather be regarded as a call for further research on the effects of IMT as an adjunct to PRP in patients with COPD. These studies will be needed to identify the best candidates for this adjunctive treatment. Based on the existing evidence and our own experience we formulate the following recommendations for further research:
1. Select patients with respiratory muscle weakness and possibly exclude or stratify those patients who are unable to dynamically hyperinflate due to severe static lung hyperinflation.
2. Tightly control adherence with and quality of the adjunct IMT intervention.
3. Tightly control symptom based progression of general exercise training intensity during the PRP and preferably allow enough time (> 8 weeks) for effects of IMT on symptom perception to establish.
4. Have general exercise training intervention executed and monitored by highly trained professionals who are blinded to group allocation.
5. Select changes in symptoms of dyspnea (MDP scores or Borg CR-10 Scale dyspnea score) at standardized levels of exertion during constant work rate endurance exercise tests as the primary outcome of these studies30 36.
References
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2. Beaumont M, Mialon P, Le Ber C, et al. Effects of inspiratory muscle training on dyspnoea in severe COPD patients during pulmonary rehabilitation: controlled randomised trial. Eur Respir J 2018;51(1) doi: 10.1183/13993003.01107-2017 [published Online First: 2018/01/27]
3. Schultz K, Jelusic D, Wittmann M, et al. Inspiratory muscle training does not improve clinical outcomes in 3-week COPD rehabilitation: results from a randomised controlled trial. Eur Respir J 2018;51(1) doi: 10.1183/13993003.02000-2017 [published Online First: 2018/01/27]
4. Charususin N, Gosselink R, Decramer M, et al. Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD. Thorax 2018 doi: 10.1136/thoraxjnl-2017-211417 [published Online First: 2018/06/20]
5. Ambrosino N. The case for inspiratory muscle training in COPD. Eur Respir J 2011;37(2):233-35.
6. Beaumont M, Forget P, Couturaud F, et al. Effects of inspiratory muscle training in COPD patients: A systematic review and meta-analysis. Clin Respir J 2018 doi: 10.1111/crj.12905 [published Online First: 2018/04/18]
7. Sonetti DA, Wetter TJ, Pegelow DF, et al. Effects of respiratory muscle training versus placebo on endurance exercise performance. Respir Physiol 2001;127(2-3):185-99. [published Online First: 2001/08/16]
8. Illi SK, Held U, Frank I, et al. Effect of respiratory muscle training on exercise performance in healthy individuals: a systematic review and meta-analysis. Sports Med 2012;42(8):707-24. doi: 10.2165/11631670-000000000-00000 [published Online First: 2012/07/07]
9. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188(8):e13-e64.
10. Camillo CA, Osadnik CR, van Remoortel H, et al. Effect of "add-on" interventions on exercise training in individuals with COPD: a systematic review. ERJ Open Res 2016;2(1) doi: 10.1183/23120541.00078-2015
11. Puhan MA, Mador MJ, Held U, et al. Interpretation of treatment changes in 6-minute walk distance in patients with COPD. Eur Respir J 2008;32(3):637-43. doi: 10.1183/09031936.00140507 [published Online First: 2008/06/14]
12. Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol 1976;41(4):508-16.
13. Morrissey MC, Harman EA, Johnson MJ. Resistance training modes: specificity and effectiveness. Med Sci Sports Exerc 1995;27(5):648-60. [published Online First: 1995/05/01]
14. Romer LM, McConnell AK. Specificity and reversibility of inspiratory muscle training. Med Sci Sports Exerc 2003;35(2):237-44. doi: 10.1249/01.MSS.0000048642.58419.1E [published Online First: 2003/02/06]
15. Gosselink R, De Vos J, van den Heuvel SP, et al. Impact of inspiratory muscle training in patients with COPD: what is the evidence? Eur Respir J 2011;37(2):416-25.
16. Gea J, Pascual S, Casadevall C, et al. Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings. J Thorac Dis 2015;7(10):E418-38. doi: 10.3978/j.issn.2072-1439.2015.08.04 [published Online First: 2015/12/02]
17. Barreiro E, Bustamante V, Cejudo P, et al. Guidelines for the evaluation and treatment of muscle dysfunction in patients with chronic obstructive pulmonary disease. Arch Bronconeumol 2015;51(8):384-95. doi: 10.1016/j.arbres.2015.04.011 [published Online First: 2015/06/15]
18. Langer D, Ciavaglia C, Webb K, et al. Inspiratory muscle weakness in mildly- to moderately-hyperinflated patients with COPD. Eur Respir J 2014;44:Suppl 58:3344.
19. Martinez FJ, Couser JI, Celli BR. Factors influencing ventilatory muscle recruitment in patients with chronic airflow obstruction. Am Rev Respir Dis 1990;142(2):276-82. doi: 10.1164/ajrccm/142.2.276 [published Online First: 1990/08/01]
20. Nava S, Ambrosino N, Crotti P, et al. Recruitment of some respiratory muscles during three maximal inspiratory manoeuvres. Thorax 1993;48(7):702-7. [published Online First: 1993/07/01]
21. Hart N, Sylvester K, Ward S, et al. Evaluation of an inspiratory muscle trainer in healthy humans. Respir Med 2001;95(6):526-31.
22. Fitting JW, Bradley TD, Easton PA, et al. Dissociation between diaphragmatic and rib cage muscle fatigue. J Appl Physiol (1985) 1988;64(3):959-65. doi: 10.1152/jappl.1988.64.3.959 [published Online First: 1988/03/01]
23. Hershenson MB, Kikuchi Y, Tzelepis GE, et al. Preferential fatigue of the rib cage muscles during inspiratory resistive loaded ventilation. J Appl Physiol (1985) 1989;66(2):750-4. doi: 10.1152/jappl.1989.66.2.750 [published Online First: 1989/02/01]
24. Segizbaeva MO, Donina Zh A, Timofeev NN, et al. EMG analysis of human inspiratory muscle resistance to fatigue during exercise. Adv Exp Med Biol 2013;788:197-205. doi: 10.1007/978-94-007-6627-3_29 [published Online First: 2013/07/10]
25. Dempsey JA, Romer L, Rodman J, et al. Consequences of exercise-induced respiratory muscle work. Respir Physiol Neurobiol 2006;151(2-3):242-50.
26. LeBlanc P, Summers E, Inman MD, et al. Inspiratory muscles during exercise: a problem of supply and demand. J Appl Physiol 1988;64(6):2482-89.
27. Luo YM, Hopkinson NS, Polkey MI. Tough at the top: must end-expiratory lung volume make way for end-inspiratory lung volume? Eur Respir J 2012;40(2):283-85.
28. Langer D, Ciavaglia CE, Faisal A, et al. Inspiratory muscle training reduces diaphragm activation and dyspnea during exercise in COPD. J Appl Physiol (1985) 2018 doi: 10.1152/japplphysiol.01078.2017 [published Online First: 2018/03/16]
29. Dekhuijzen PN, Folgering HT, van Herwaarden CL. Target-flow inspiratory muscle training during pulmonary rehabilitation in patients with COPD. Chest 1991;99(1):128-33.
30. Ekstrom M, Elmberg V, Lindow T, et al. Breathlessness measurement should be standardised for the level of exertion. Eur Respir J 2018;51(5) doi: 10.1183/13993003.00486-2018 [published Online First: 2018/06/01]
31. Puhan MA, Schunemann HJ, Frey M, et al. Value of supplemental interventions to enhance the effectiveness of physical exercise during respiratory rehabilitation in COPD patients. A systematic review. Respir Res 2004;5:25. doi: 10.1186/1465-9921-5-25 [published Online First: 2004/12/04]
32. Laviolette L, Bourbeau J, Bernard S, et al. Assessing the impact of pulmonary rehabilitation on functional status in COPD. Thorax 2008;63(2):115-21. doi: 10.1136/thx.2006.076844 [published Online First: 2007/09/29]
33. Pepin V, Brodeur J, Lacasse Y, et al. Six-minute walking versus shuttle walking: responsiveness to bronchodilation in chronic obstructive pulmonary disease. Thorax 2007;62(4):291-8. doi: 10.1136/thx.2006.065540 [published Online First: 2006/11/14]
34. Guenette JA, Webb KA, O'Donnell DE. Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD? Eur Respir J 2012;40(2):322-29.
35. Langer D, Charususin N, Jacome C, et al. Efficacy of a Novel Method for Inspiratory Muscle Training in People With Chronic Obstructive Pulmonary Disease. Phys Ther 2015;95(9):1264-73. doi: ptj.20140245 [pii];10.2522/ptj.20140245 [doi]
36. Beaumont M, Mialon P, Couturaud F. Breathlessness measurement should be standardised for the level of exertion. Eur Respir J 2018;51(5) doi: 10.1183/13993003.00820-2018 [published Online First: 2018/06/01]
Science is the great antidote to the poison of enthusiasm and superstition
We thank Langer and colleagues for their interest in our editorial. In many ways the title they have chosen for their response confirms our thesis. ‘Absence of evidence’ may not be ‘Evidence of absence’ but it is ……………….. Absence of evidence . Our contention overall is that the relentless search for benefit despite the recently reported negative trials is driven by emotion rather than data.
Whilst physiological arguments are of interest to physiologists, there remains no convincing evidence in our view either that respiratory muscle fatigue is present in patients with COPD, or that it contributes to exercise limitation. The various suggestions they make in the hope of eliciting a ‘positive result’ for IMT (e.g. changing outcome measure, patient selection) are credible research suggestions and we would not oppose interested investigators pursuing research in this arena, but this does not alter our contention that IMT has no place in current clinical practice.
Clinically their argument is that IMT alone is beneficial in COPD. We think this argument is specious (irrespective of whether it is correct); pulmonary rehabilitation, in part thanks to the Leuven group, has one of the strongest evidence bases for any therapy in COPD. Therefore the idea that one might drop PR in order to do IMT instead is not one we believe should be taken into the clinical arena....
Science is the great antidote to the poison of enthusiasm and superstition
We thank Langer and colleagues for their interest in our editorial. In many ways the title they have chosen for their response confirms our thesis. ‘Absence of evidence’ may not be ‘Evidence of absence’ but it is ……………….. Absence of evidence . Our contention overall is that the relentless search for benefit despite the recently reported negative trials is driven by emotion rather than data.
Whilst physiological arguments are of interest to physiologists, there remains no convincing evidence in our view either that respiratory muscle fatigue is present in patients with COPD, or that it contributes to exercise limitation. The various suggestions they make in the hope of eliciting a ‘positive result’ for IMT (e.g. changing outcome measure, patient selection) are credible research suggestions and we would not oppose interested investigators pursuing research in this arena, but this does not alter our contention that IMT has no place in current clinical practice.
Clinically their argument is that IMT alone is beneficial in COPD. We think this argument is specious (irrespective of whether it is correct); pulmonary rehabilitation, in part thanks to the Leuven group, has one of the strongest evidence bases for any therapy in COPD. Therefore the idea that one might drop PR in order to do IMT instead is not one we believe should be taken into the clinical arena.
Lastly we very much hope to be proved wrong by Dr Langer’s future research; if IMT could be shown to confer benefit in a sub-population of COPD patients we entirely accept that it would be a cheap and low risk therapy
With best wishes
Michael Polkey and Nicolino Ambrosino
(Quote from Adam Smith, The Wealth of Nations 1776)
The differentiation between an empyema and a peripheral lung abscess is really difficult. The authors have summarized most points on differentiation. We had of a similar case, which looked like an Abscess on Chest Xray and had Acute angulation with lungs on Chest Ct, but due to the smooth inner walls and enhancement of pleura, we treated the case like an Empyema. Interestingly the initial CT showed some volume loss with ribs appearing crowded and this feature was more pronounced in the subsequent CT done after 2 weeks. Thus, associated volume loss with rib crowding could also be an additional point in the differentiation favoring Empyema and this volume loss might appear fairly early as well.
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
This study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the fac...
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
This study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the factors cited by our physiotherapists include patient fatigue, limitations on staff availability and also clinical appropriateness of the patients for rehabilitation. Of interest, Schaller et al. have also suggested some solutions to the problems encountered in our own audit and also within the EPICC trial. We agree that the combined effort of the multi-disciplinary team is extremely important in order to maximise opportunities for rehabilitation sessions but also the ability to then consider multiple short sessions each day.
In summary, we applaud the attempts of Wright and colleagues for addressing this under-investigated area of rehabilitation. We have reservations about some of the conclusions of the paper due to limited differences between intervention and treatment and underpowering of the study. Our own unpublished data supports the finding that to consistently achieve 90 minutes of therapy per patient as stipulated for the intervention group in this study would be very difficult in the current framework but this is an area to improve with some solutions already suggested.
References:
1. Wright SE, Thomas K, Watson G, et al. Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial. Thorax 2017:thoraxjnl-2016-209858
2. Schaller SJ, Nydahl P, Blobner M, et al. What does the EPICC trial really tell us? Thorax 2018
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...
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 screening intervals that was based on baseline LDCT findings. Given the small sample of this trial, we underline that the absence of outcome difference between LDCT1 and LDCT2 should be carefully interpreted (5).
In summary, baseline LDCT2 prospectively selected 147/1,151 (12.8%) screenees for annual screening, whilst 1,004/1,151 (87.2%) were forwarded to biennial round (6). The LDCT2 risk model allowed a sharp reduction by almost 90% LDCTs at the first incidence round. This is a considerable proportion compared to the retrospective analysis presented by Schreuder et al (simulations led to potential LDCT reduction ranging from 10.4% to 81.6%) (3). A similar figure was seen every other year throughout 7.3 years, with overall cuts of 32% LDCTs in LDCT2 compared with LDCT1 (6).
We would like to emphasize that the volumetric risk model allowed higher detection rate in LDCT2 screenees selected for annual screening (1.36% namely 2 lung cancers in 147 screenees) compared to LDCT1 screenees (0.45% namely 5 lung cancers in 1,111 screenees), at the first annual LDCT after baseline. Under this prospective condition, the number of scans needed to diagnose one lung cancer case (NND) was 74 in LDCT2, which is quite close to the 60 NND proposed by Schreuder by accepting a delay of diagnosis in 25% of screenees. On the other hand, NND was 222.2 in LDCT1, namely within the NND range reported in the literature (from 125 to 385) at the first annual LDCT by fixed annual screening algorithms (1, 7, 8). Hence, the LDCT2 algorithm prompted the lowest prospective NND reported in the literature. Through the median 7.3 years of LDCT screening in MILD, the cumulative NND during annual screenings was 63 for selected LDCT2 screenees and 250 for LDCT1 (p=0.003). Selective 3-year screening interval is now being tested in the bioMILD trial with higher volumetric threshold for solid nodules and including circulating biomarkers (ClinicalTrials.gov: NCT02247453; >4,000 baseline LDCTs acquired, results expected by 2020).
We hypothesize that the prospective application of Schreuder’s model might even improve the efficiency of MILD LDCT2. Furthermore, enrichment by clinical variables is encouraged, including circulating biomarkers. More models like Schreuder’s are fostered for optimization of radiologists’ workload for the seemingly approaching practice of population-based lung cancer screening by LDCT.
References
1. National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. The New England journal of medicine. 2011;365(5):395-409.
2. Patz EF, Jr., Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. The Lancet Oncology. 2016;17(5):590-9.
3. Schreuder A, Schaefer-Prokop CM, Scholten ET, Jacobs C, Prokop M, van Ginneken B. Lung cancer risk to personalise annual and biennial follow-up computed tomography screening. Thorax. 2018.
4. White CS, Dharaiya E, Campbell E, Boroczky L. The Vancouver Lung Cancer Risk Prediction Model: Assessment by Using a Subset of the National Lung Screening Trial Cohort. Radiology. 2017;283(1):264-72.
5. Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation. 2012;21(3):308-15.
6. Sverzellati N, Silva M, Calareso G, Galeone C, Marchiano A, Sestini S, et al. Low-dose computed tomography for lung cancer screening: comparison of performance between annual and biennial screen. European radiology. 2016;26(11):3821-9.
7. Yousaf-Khan U, van der Aalst C, de Jong PA, Heuvelmans M, Scholten E, Walter J, et al. Risk stratification based on screening history: the NELSON lung cancer screening study. Thorax. 2017.
8. Tammemagi MC, Schmidt H, Martel S, McWilliams A, Goffin JR, Johnston MR, et al. Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study. The Lancet Oncology. 2017.
The National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrain...
Show MoreThe global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Show MoreMany respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patie...
We read with interest the findings of Miele et al. on the relationship between environmental exposures and decline in lung function (1). The authors reported that living in urban settings and living at high altitude were associated with accelerated decline in pre-bronchodilator FEV1 and FVC. Investigating the effects at area level is important from a public health perspective and extra analysis on this valuable dataset as suggested below will help to untangle these links further.
Show MoreStudy participants were recruited from four settings in Peru: Lima, Tumbles, urban Puno and rural Puno (1). Urban living and high-altitude dwelling (as binary variables) were defined based on these four settings. The authors compared the effect of urban living (Lima and urban Puno) with rural living (Tumbes and rural Puno); and the effect of high-altitude dwelling (urban Puno and rural Puno) with low-altitude dwelling (Lima and Tumbes). It is possible that the observed independent effects found by the authors of urban living and high-altitude dwelling may be driven by the urban Puno group (high altitude and urban living). In other words, there may be an interaction between urban living and high-altitude dwelling and investigating this potential interaction would be informative.
As discussed by the authors, the adverse effect of high-altitude dwelling on lung function decline may partly be related to hypoxia and adverse effects from living in urban settings may be related to outdoor air...
According to recent study published by Sebastian et al., (1) electronic cigarette vapor impairs the activity of alveolar macrophages, which engulf and remove dust particles, bacteria, and allergens that have evaded the other mechanical defenses of the respiratory tract. This study finding is important and it shows that the long term health impact of e-cigarettes use may be more harmful than we know (2).
Meanwhile, industry, tobacco research community and the online information are promoting electronic cigarette as a less harmful tobacco cessation tool. However, before more leeway to advertise the harm-reduction benefits of vaping products, we believe that the first step would be to establish whether vaping products are indeed safer tobacco cessation device or harm reduction tool (3). Moreover, currently available evidence (including clinical guidelines and position statements of credible medical organizations) based information need to ensure that people are protected from commercial interests and are able to make informed decisions based on current best evidence on electronic cigarette and its long term health effects (3). It is our moral obligation that we should not be promoted electronic cigarette to our children and people those who never wanted to smoke tobacco. At the same time, it is important to promote the proven non-tobacco nicotine products such as Nicotine Replacement Therapy (gum or inhalators) to smokers those who are sincerely wanted to quit.
...Show MoreAlthough electronic cigarettes (ECs) are a much less harmful alternative to tobacco cigarettes, there is concern as to whether long-term ECs use may cause risks to human health. There are reasonable concerns and should be elucidated as soon as possible to learn how to best employ these products, causing the least possible damage to users.
Show MoreScott and colleagues aimed at define whether e-cig vapors have a negative impact on human alveolar macrophages (AMs) viability and function (1). They tested human AMs from lung resection specimens from healthy donors by exposing these cells to the electronic cigarette vapour condensate (ECVC).
First of all, the authors dedicated a detailed explanation to the method used to condensate the vapour, but the protocol used to generate vapour is quite ambiguous, omitting to indicate puff volume, puff number, and in particular if the pump used to aspirate the vapors were able to generate the correct puff profile (2). This is a crucial step in the validation process of an exposure method, because if the vapours are generated with incorrect regimes, they can lead to the production of inaccurate ECVC and thus to distorted results invalidating all the conclusions of the study. We think the author could detail the regimen employed for vapour generation.
Furthermore, airway macrophages are resident in the connective tissue and not exposed directly to the liquid-air interface, therefore the method used for the exposition of these cells...
We support the view of Drs. Polkey and Ambrosino that recommendations for clinical practice should not be based on either positive or negative preoccupation concerning the potential effectiveness of a treatment but rather on an impartial evaluation of the available data. In their editorial entitled ‘Inspiratory Muscle Training in COPD: can data finally beat emotion’ they unfortunately provide a fairly one-sided evaluation of this treatment, based on an incomplete and largely outdated review of the available evidence1. It is unfortunate that they neglect a major part of available data, which could contribute to a more balanced and fair discussion about this intervention. We therefore deemed it necessary to add this missing evidence along with our own interpretation of recent findings to the discussion.
Show MoreComplexity of studying add-on interventions to pulmonary rehabilitation
Based on the results from three recent multicentre trials2-4, Polkey and Ambrosino exclude a role for adjunctive IMT in the rehabilitation of patients with COPD. As emphasized in a previous opinion piece by Dr. Ambrosino5, it is important to distinguish between studies that evaluate the effects of inspiratory muscle training (IMT) as a standalone intervention (i.e. in comparison to no intervention or a sham control intervention) and studies on the effects of IMT added to a pulmonary rehabilitation program (PRP).
Concerning the first comparison, there is a large amount of data available s...
To the Editor
Science is the great antidote to the poison of enthusiasm and superstition
We thank Langer and colleagues for their interest in our editorial. In many ways the title they have chosen for their response confirms our thesis. ‘Absence of evidence’ may not be ‘Evidence of absence’ but it is ……………….. Absence of evidence . Our contention overall is that the relentless search for benefit despite the recently reported negative trials is driven by emotion rather than data.
Show MoreWhilst physiological arguments are of interest to physiologists, there remains no convincing evidence in our view either that respiratory muscle fatigue is present in patients with COPD, or that it contributes to exercise limitation. The various suggestions they make in the hope of eliciting a ‘positive result’ for IMT (e.g. changing outcome measure, patient selection) are credible research suggestions and we would not oppose interested investigators pursuing research in this arena, but this does not alter our contention that IMT has no place in current clinical practice.
Clinically their argument is that IMT alone is beneficial in COPD. We think this argument is specious (irrespective of whether it is correct); pulmonary rehabilitation, in part thanks to the Leuven group, has one of the strongest evidence bases for any therapy in COPD. Therefore the idea that one might drop PR in order to do IMT instead is not one we believe should be taken into the clinical arena....
The differentiation between an empyema and a peripheral lung abscess is really difficult. The authors have summarized most points on differentiation. We had of a similar case, which looked like an Abscess on Chest Xray and had Acute angulation with lungs on Chest Ct, but due to the smooth inner walls and enhancement of pleura, we treated the case like an Empyema. Interestingly the initial CT showed some volume loss with ribs appearing crowded and this feature was more pronounced in the subsequent CT done after 2 weeks. Thus, associated volume loss with rib crowding could also be an additional point in the differentiation favoring Empyema and this volume loss might appear fairly early as well.
****can provide CT films of the same****
The EPICC trial addresses the rarely investigated topic of rehabilitation in the critical care setting [1]. We note with interest that no improvement was found in outcomes in the rehabilitation group compared to the standard treatment group. Some of the reasons are clearly highlighted by Schaller et al. in their response to the paper including the time to starting intervention, therapy times and also sample size. Only 41% of the participants in the intervention group and 35% of the standard treatment group contributed data throughout the study period. In addition to this, only 8% of the intervention group managed over half the target therapy time and the EPICC trial showed that ‘an extra 10 minutes of physical therapy per day does not make a difference [2]’
Show MoreThis study triggered an audit within our own 16 bedded mixed surgical and medical intensive care department assessing the number of sessions carried out over a 2 week period compared to those attempted. We investigated the actual duration of sessions achieved as compared to a target of 45 minutes rehabilitation each day during the working week (Monday-Friday). On average, 23.3 (standard deviation 20.19 minutes) minutes of rehabilitation per day was achieved and only 35% of attempted physical therapy sessions were completed. These figures are similar to those cited within the EPICC trial and highlight some of the difficulties of achieving longer therapy times within a busy intensive care department. Some of the fac...
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).
Show MoreSchreuder 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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