We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.
We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.
Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates i...
We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.
We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.
Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates included were sex, age at NIV introduction, and variables with a p value <0.15 in the univariate analysis identified by progressive selection (also included in the online repository).
In univariate analysis, having a pacemaker was not significantly associated with mortality. All our DM1 patients are systematically explored in a specialised cardiologic ward [1] which belongs to the same reference center for neuromuscular patients as our unit [2]; therefore patients with diagnosed heart conduction disturbances underwent pacemaker placement [3], which limited their risk of death from cardiac causes. Regarding functional status, all patients were walking.
One of the main objectives of ventilatory support is to improve gas exchanges regardless the mechanism (respiratory pump failure or respiratory drive dysfunction), which means the normalization of PaCO2, and to improve the signs and symptoms, which has already been demonstrated by Nugent and al [4]. However, the aim of our study was to identify the long term impact of mechanical ventilation, and not its short-term effectiveness. Our usual follow-up aims to ensure that patients are well ventilated within the first 3 months of treatment initiation. During nighttime, and daytime when required, both ventilator settings and interfaces are adjusted using repeated polygraphies (with transcutaneous PCO2), or polysomnographies [5, 6] when necessary, until patients-ventilator interaction is correct and nocturnal transcutaneous PCO2 improves. Moreover, we also use pharmacological treatments when residual daytime hypersomnolence is due solely to central neurological dysfunction [7, 8], as our specialised sleep laboratory is also certified as a reference centre for daytime sleepiness, where we can objectively evaluate daytime sleepiness and efficiency of different treatments by Multiple Sleep Latency Tests and/or the Maintenance of Wakefulness Tests [9]. NIV and sleep were usually efficient within the first months and were controlled every year [6] when patients accepted to continue mechanical ventilation and to come back. Therefore, it was not our objective to prove the effectiveness of mechanical ventilation in this manuscript, considering that at this stage the most important factor, in our opinion, is the adherence to treatment.
In conclusion, the main limit of this study is that it involved a single-center which limits the generalization of the findings. However, because there is no data in the literature regarding the long term impact of mechanical ventilation on DM1 patients survival, this study could be considered as the first report on which to base larger, multicenter studies as suggested by Dr. Seijger and colleagues.
Reference
[1] Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Bécane HM, Lazarus A, Béhin A, Laforêt P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2017 Mar 7;38(10):751-758.
[2] Boussaïd G, Wahbi K, Laforet P, Eymard B, Stojkovic T, Behin A, Djillali A,
Orlikowski D, Prigent H, Lofaso F. Genotype and other determinants of respiratory function in myotonic dystrophy type 1. Neuromuscul Disord. 2018 Mar;28(3):222-228.
[3] Wahbi K, Meune C, Porcher R, Bécane HM, Lazarus A, Laforêt P, Stojkovic T, Béhin A, Radvanyi-Hoffmann H, Eymard B, Duboc D. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA. 2012 Mar 28;307(12):1292-301.
[4] Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest. 2002 Feb;121(2):459-64.
[5] Nardi J, Prigent H, Garnier B, Lebargy F, Quera-Salva MA, Orlikowski D, Lofaso F. Efficiency of invasive mechanical ventilation during sleep in Duchenne muscular dystrophy. Sleep Med. 2012 Sep;13(8):1056-65.
[6] Annane D, Quera-Salva MA, Lofaso F, Vercken JB, Lesieur O, Fromageot C, Clair B, Gajdos P, Raphael JC. Mechanisms underlying effects of nocturnal ventilation on daytime blood gases in neuromuscular diseases. Eur Respir J. 1999 Jan;13(1):157-62.
[7] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.
[8] Hilton-Jones D, Bowler M, Lochmueller H, Longman C, Petty R, Roberts M, Rogers M, Turner C, Wilcox D. Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1--the patients' perspective. Neuromuscul Disord. 2012 Jul;22(7):597-603.
[9] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.
We read with great interest the paper of Boussaïd et al.1. They showed that Myotonic Dystrophy type 1 (DM1) patients who refused or delayed non-invasive ventilation were at higher risk for severe events, the latter defined as invasive ventilation or death. In the NIV users, risk of death was associated with orthopnoea and adherence to therapy. The investigators concluded that non-use or poor adherence of home mechanical ventilation (HMV) may be associated with increased mortality. Despite the importance of these findings several comments can be made.
First, survival analyses in DM1 patients are complex due to heterogeneity and several other factors which have to be taken into account if the effects of HMV are assessed. For example not only the variance of reduced pulmonary function but also neuromuscular deficits, apathy, cardiac conduction disturbances, presence of obstructive or central sleep apnea do all influence the clinical condition and prognosis of these patients2. In addition, there remains the possibility that hypercapnia might not always be a result of ventilatory pump failure and that HMV might not be effective3. Correction for these confounders is needed to investigate the real effect of HMV. Moreover, both groups differ in vital capacity and presence of hypercapnia at baseline. So, we are not sure whether the risk of a severe event is really higher in the l/noNIV group than in the other groups. Therefore the presented difference...
We read with great interest the paper of Boussaïd et al.1. They showed that Myotonic Dystrophy type 1 (DM1) patients who refused or delayed non-invasive ventilation were at higher risk for severe events, the latter defined as invasive ventilation or death. In the NIV users, risk of death was associated with orthopnoea and adherence to therapy. The investigators concluded that non-use or poor adherence of home mechanical ventilation (HMV) may be associated with increased mortality. Despite the importance of these findings several comments can be made.
First, survival analyses in DM1 patients are complex due to heterogeneity and several other factors which have to be taken into account if the effects of HMV are assessed. For example not only the variance of reduced pulmonary function but also neuromuscular deficits, apathy, cardiac conduction disturbances, presence of obstructive or central sleep apnea do all influence the clinical condition and prognosis of these patients2. In addition, there remains the possibility that hypercapnia might not always be a result of ventilatory pump failure and that HMV might not be effective3. Correction for these confounders is needed to investigate the real effect of HMV. Moreover, both groups differ in vital capacity and presence of hypercapnia at baseline. So, we are not sure whether the risk of a severe event is really higher in the l/noNIV group than in the other groups. Therefore the presented difference might be due to differences in baseline covariates such as age at first visit, pulmonary function or other factors.
Second, one of the main goals of ventilatory support is to improve gas-exchange, which means normalisation of the CO2, and to improve signs and symptoms. However, we do not know whether HMV was effective in this study, as information about CO2 reduction during HMV is not presented. Therefore, we have to be careful with strong conclusions.
Finally, as patients who accepted NIV late or not at all are combined in one group in figure 1, it is not possible to distinguish differences in prognosis between these subgroups. In addition, figure 1 is confusing as the title suggests a mortality curve, but an event is defined as invasive ventilation or death. Also it is unclear which line belongs to which subgroup as the legend of the figure is missing.
In conclusion, the heterogeneity of DM1 requests for correction of several covariates in statistical analyses. Without these considerations, we must be careful in interpreting the results of this study and we recommend that new studies about the effects of HMV in DM1 must take these heterogeneity aspects into account.
References
1. Boussaid G, Prigent H, Laforet P, et al. Effect and impact of mechanical ventilation in myotonic dystrophy type 1: A prospective cohort study. Thorax. 2018;73(11):1075-1078.
2. Turner C, Hilton-Jones D. The myotonic dystrophies: Diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81(4):358-367.
3. West SD, Lochmuller H, Hughes J, et al. Sleepiness and sleep-related breathing disorders in myotonic dystrophy and responses to treatment: A prospective cohort study. J Neuromuscul Dis. 2016;3(4):529-537.
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.
Lommatzsch et al1 report significant falls in blood eosinophils in 11 asthma patients (mean FEV1 87%) in response to increasing the dose of inhaled corticosteroid from 1000ug to 2000ug/day (beclometasone equivalent dose ) ,with a median difference of 240 cells/ul . Jabbal et al 2 reported in 217 asthma patients (FEV1 85%) a mean fall of 71 cells/ul (95%CI 38-105) comparing 200ug verses 800ug belcometasone equivalent dose ,along with a 14.5ppb (95%CI 7.9-22.1) fall in FeNO. The patients reported by Lommatzsch et al had a higher baseline level of eosinophils with a median value of 560 cells/ul as compared to a mean value 356 cells/ul for Jabbal et al . Nonetheless we agree with the conclusion that the prevailing inhaled corticosteroid dose should be taken into consideration when making decisions to initiate treatment with biologics such as anti-IL5 and anti-IL4α, where the response is determined by levels of blood eosinophils .
References
1. Lommatzsch M, Klein M, Stoll P, Virchow JC. Impact of an increase in the inhaled corticosteroid dose on blood eosinophils in asthma. Thorax 2018. doi:10.1136/thoraxjnl-2018-212233
2. Jabbal S, Lipworth BJ. Blood eosinophils: The forgotten man of inhaled steroid dose titration. Clin Exp Allergy 2018; 48:93-5.
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)
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
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 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
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.
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.
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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]
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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]
We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.
We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.
Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates i...
Show MoreTo the editor,
We read with great interest the paper of Boussaïd et al.1. They showed that Myotonic Dystrophy type 1 (DM1) patients who refused or delayed non-invasive ventilation were at higher risk for severe events, the latter defined as invasive ventilation or death. In the NIV users, risk of death was associated with orthopnoea and adherence to therapy. The investigators concluded that non-use or poor adherence of home mechanical ventilation (HMV) may be associated with increased mortality. Despite the importance of these findings several comments can be made.
First, survival analyses in DM1 patients are complex due to heterogeneity and several other factors which have to be taken into account if the effects of HMV are assessed. For example not only the variance of reduced pulmonary function but also neuromuscular deficits, apathy, cardiac conduction disturbances, presence of obstructive or central sleep apnea do all influence the clinical condition and prognosis of these patients2. In addition, there remains the possibility that hypercapnia might not always be a result of ventilatory pump failure and that HMV might not be effective3. Correction for these confounders is needed to investigate the real effect of HMV. Moreover, both groups differ in vital capacity and presence of hypercapnia at baseline. So, we are not sure whether the risk of a severe event is really higher in the l/noNIV group than in the other groups. Therefore the presented difference...
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...
Lommatzsch et al1 report significant falls in blood eosinophils in 11 asthma patients (mean FEV1 87%) in response to increasing the dose of inhaled corticosteroid from 1000ug to 2000ug/day (beclometasone equivalent dose ) ,with a median difference of 240 cells/ul . Jabbal et al 2 reported in 217 asthma patients (FEV1 85%) a mean fall of 71 cells/ul (95%CI 38-105) comparing 200ug verses 800ug belcometasone equivalent dose ,along with a 14.5ppb (95%CI 7.9-22.1) fall in FeNO. The patients reported by Lommatzsch et al had a higher baseline level of eosinophils with a median value of 560 cells/ul as compared to a mean value 356 cells/ul for Jabbal et al . Nonetheless we agree with the conclusion that the prevailing inhaled corticosteroid dose should be taken into consideration when making decisions to initiate treatment with biologics such as anti-IL5 and anti-IL4α, where the response is determined by levels of blood eosinophils .
References
1. Lommatzsch M, Klein M, Stoll P, Virchow JC. Impact of an increase in the inhaled corticosteroid dose on blood eosinophils in asthma. Thorax 2018. doi:10.1136/thoraxjnl-2018-212233
2. Jabbal S, Lipworth BJ. Blood eosinophils: The forgotten man of inhaled steroid dose titration. Clin Exp Allergy 2018; 48:93-5.
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....
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.
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...
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 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 MoreAccording 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 MoreWe 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...
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