It was with great interest and not a little concern that we read the recent Brief Communication by Janson and colleagues [1] into the impact of pressurised metered dose inhalers (pMDIs) on the global warming potential (GWP) of respiratory care. We note the tenacity of one of the authors who has succeeded in publishing a second paper [2] based on a similar, flawed logic just two weeks later. The sense of proportion that is missing in both reports has, thankfully, been identified in the press this week.[3] However, we feel it essential to scrutinise the current contribution scientifically.
The authors report the carbon footprints of a range of devices marketed by GlaxoSmithKline (GSK) following analysis undertaken by the Carbon Trust (a UK not-for dividend company). Subsequently, calculations were undertaken aimed to determine how the carbon footprint of inhalation therapy in the UK’s National Health Service (NHS) might be reduced by altering the prescribing patterns of UK physicians (where more pMDIs are prescribed than dry powder inhalers (DPIs)) to resemble those of Swedish physicians (where the converse holds). While we acknowledge the authors’ declaration that their data are potentially flawed by the fact that their calculations are based on extrapolating the carbon footprints of just three device formats manufactured by one company to predict the effects of total DPI and pMDI usage in the UK when the carbon footprints of most other devices are unknown, we wou...
It was with great interest and not a little concern that we read the recent Brief Communication by Janson and colleagues [1] into the impact of pressurised metered dose inhalers (pMDIs) on the global warming potential (GWP) of respiratory care. We note the tenacity of one of the authors who has succeeded in publishing a second paper [2] based on a similar, flawed logic just two weeks later. The sense of proportion that is missing in both reports has, thankfully, been identified in the press this week.[3] However, we feel it essential to scrutinise the current contribution scientifically.
The authors report the carbon footprints of a range of devices marketed by GlaxoSmithKline (GSK) following analysis undertaken by the Carbon Trust (a UK not-for dividend company). Subsequently, calculations were undertaken aimed to determine how the carbon footprint of inhalation therapy in the UK’s National Health Service (NHS) might be reduced by altering the prescribing patterns of UK physicians (where more pMDIs are prescribed than dry powder inhalers (DPIs)) to resemble those of Swedish physicians (where the converse holds). While we acknowledge the authors’ declaration that their data are potentially flawed by the fact that their calculations are based on extrapolating the carbon footprints of just three device formats manufactured by one company to predict the effects of total DPI and pMDI usage in the UK when the carbon footprints of most other devices are unknown, we would suggest that this is not the only potential weakness of the analysis. It is also erroneous to compare the UK to Sweden by looking solely at prescribing data for England, and not the entire UK. The modelling of GSK-GSK product switches ignored that there may be both lower GWP and lower cost alternative DPIs or inhalation device formats. Indeed, we are deeply concerned the reports by such respected authors could be interpreted as promoting a commercial bias of one company recommending switching patients to their own – frequently more expensive – products to save the planet, where there could be both lower carbon footprint and lower cost from alternatives.
This is the second occasion that we have felt obliged to respond to such analysis and invite scientists and clinicians to clamour for independent assessment of the multiple ramifications of developing medicine that is both effective and environmentally sustainable.[4] An additional incorrect assumption perpetuated in this second article, that has direct clinical consequences for respiratory disease patients, is that all patients can be summarily switched from pMDIs to DPI therapy irrespective of their age, the nature and severity of their obstructive airway disease, or ability to use DPIs efficiently. We would remind readers that healthcare professionals must consider many therapeutic factors when selecting the most appropriate inhaler device for individual patients if they wish treatment to be effective. For example, DPIs, are seldom appropriate for use in young children, the elderly and infirm and those with considerable, irreversible airways obstruction.[5] The authors’ data does not differentiate between asthma and COPD prescriptions. Several clinical modelling assumptions in the current Brief Communication are therefore unrealistic and undermine the data in their article. Of significant concern is their calculation based on 2 doses of short-acting beta agonist (SABA) a day. If these are asthma patients, then the pMDI-DPI switch is poor practice and the prescribing signifies uncontrolled asthma (likely because regular inhaled corticosteroids (ICS) are not being taken, or device use is incorrect), and it further indicates the need for an urgent healthcare professional review to reassess medication, inhaler device, inhaler technique, adherence and patient motivation.[6, 7]
We agree wholeheartedly with the authors that it is necessary to take an environmentally sustainable approach to prescribing. However we have grave reservations about the assertion that switching patients’ from pMDIs to the cheapest DPIs would result in large carbon savings, while ignoring the carbon impact during manufacture of devices (not included in their limited modelling), and possible consequences for loss of disease control and consequent morbidity and mortality from obstructive airways diseases such as asthma.
We note that the authors only report the carbon footprint of several of GSK’s product range, rather than undertaking an holistic lifecycle analysis of the products.[8] Such an analysis was performed by Jeswani and Azapagic for pMDIs made with the propellants HFA134, HFA227, HFA152 and a GSK DPI-Diskus device.[9] Although the DPI outperformed the HFA134 and HFA227 pMDIs for GWP; human toxicity, marine eutrophication and fossil depletion were all concluded to be worse for DPI-Diskus than HFA-based pMDIs. In fact, the full spectrum of long-term environmental effects of DPI-Diskus were actually worse for eight out of fourteen environmental impact metrics than for pMDIs. The inhaled pharmaceutical development sector is currently examining the switchover of HFA134 and HFA227 to a low GWP alternative propellant HFA152a. Once the HFA152a switchover has been made, pMDIs will have an equivalent carbon footprint to DPIs, but have improved environmental impact profile.[9] Switchover may also present an opportunity to reduce the extent of manufacturing overfill (many “200 dose” inhalers are currently filled to between 220-240 dosages to ensure through-life stability) which would also have an impact on GWP.
When undertaking their analysis of the potential reductions in carbon emissions for individual patients and for the NHS if a pMDI-DPI switch were enacted, the authors used data from the Carbon Footprint Certification Summary Report for several GSK inhalation products [10] included in their supplementary material. While we recognise and acknowledge the invaluable and sector-leading work of the Carbon Trust, we note the authors of the current study have not facilitated close scrutiny of the primary carbon calculation methodologies, in contrast to other studies in the scientific literature (e.g. [9, 11]). Indeed, we note one of the Carbon Footprint Report’s 'Recommended Further Actions' was to: “collect accurate, recent primary data”.[10] Since we have no access to them, it is impossible for the reader to know how old and complete the data are that were presented to the Carbon Trust. Given this shortcoming, we believe it is at best unjustified, and at worst thoroughly inappropriate to predict the GWP reduction for inhalation therapy by assuming that all pMDI products on the market have the same carbon footprint as GSK’s Evohaler (20 kg CO2e), and that all prescribed DPIs possess the same GWP as the Ellipta and Diskus devices of ~1kg CO2e per device. This is patently untrue in the case of the Salamol salbutamol pMDI, for example, which has a carbon footprint which is approximately half that modelled in the current communication.[8, 11] All DPIs have widely different structures and contents in terms of parts and plastics involved in their manufacture, or the number of dose units contained in the device. As a significant contributor to GWP in DPIs is the active pharmaceutical ingredient (API),[11] it follows that the move from mono-therapy towards double and triple combinations is therefore more likely to be a move for DPIs towards higher GWP.
The authors’ comparisons between the percentage of patients prescribed pMDIs in the UK (70%) compared to Sweden (10%) extends no further than the pharmacological category of prescribed inhaler numbers in England; and does not take into account the prescribed brand (and its corresponding carbon footprint), nor the indication for the prescribed therapy. Such an assessment is a blunt tool and fails to account for potential differences in disease care pathways in each country. For example, NICE [12] and SIGN/BTS [7] guidelines advocate the use of SABA use as first line therapy for asthma, and as pMDIs are cheapest, this may account for the high levels of prescribing in England compared to other countries. There is no assessment as to whether the SABAs prescribed in Sweden are identical to those in the UK. The exercise of replicating the Swedish prescribing patterns in the UK context is undertaken with no regard to the disease(s) being treated in which (sub)-populations of patients. The authors summarily assert that that the reasons underpinning the different prescribing patterns “could be related to marketing strategies and prescribers’ and patients’ biases”. This is a remarkable conclusion from authors representing one of the world’s leading producers of inhalation medicines regarding the prescribing of their own products. Indeed, we note that the economic cost to the NHS of the switches recommended in this article would be substantial, given the higher cost of many of GSK’s DPIs compared with pMDI. [2]
We have pointed out that Janson and colleagues have assumed in their analysis that all patients in the UK can be switched from pMDI to DPI therapy regardless of fact that not all patients can use DPIs effectively (because of their age, and/or the nature or severity of their disease) and the influence of their own satisfaction with – or preference for – the switched device which is a known factor influencing therapeutic outcome.[13] In contrast to DPIs, all patients with sufficient hand motor function can use pMDIs effectively in combination with a spacer device, when well-instructed. Indeed, the pMDI combination compounds of salmeterol xinafoate with fluticasone propionate, marketed by this company, have been shown to be more effective in real life studies on improving asthma control [14] and COPD [15] disease exacerbations than the very same combination given as a DPI.
In light of the potential for loss of disease control when switching devices, it seems imperative that the carbon footprint of potential loss of disease control also be presented to healthcare professionals alongside the carbon footprint implications of the switchover itself. [16, 17] There is no assessment of the carbon footprint of the clinical visits involved in switching and re-training patients. Disease destabilisation and the associated “carbon cost” of unnecessary emergency and secondary care disease management would also be significant. For example, Goulet et al. [11] estimated that the carbon footprint of a single bronchodilator dose administered with an electric nebuliser is a considerable 0.0294-0.0477 kg CO2e, while Moorfields Eye Hospital estimated that the carbon footprint of a single patient visit was between 8-10 kg CO2e per patient, per visit. [18] Therefore, the carbon reductions described by the authors may not reflect the full costs of the switchover. We advocate face-to-face training and assessment of optimal inhaler technique to ensure patients are prescribed an inhaler device that they are able to use in order to manage their asthma or COPD, before examining the carbon footprint of a patient’s inhalation therapy as the secondary prescribing assessment.
Our final substantive objection to the approach taken by the authors in this manuscript is the comparison of the carbon footprint of a patient’s inhalation therapy to reductions achievable by lifestyle choices, such as changing from a meat-based to plant-based diet, changing transport modalities or how clothes are washed. Patients with lung disease or any other disease do not choose to have their condition, nor is it a lifestyle choice to use therapy with which best manages the condition for each individual. The flippant comparisons made in the recent report [2] resulted in newspaper headlines that potentially add to the burden of anxiety of patients by amplifying the “guilt” of contributing to climate change when taking an essential medicine. There is a need for balanced, articulate and, most importantly, accurate analysis that avoids the stigmatisation of patients with asthma and COPD through news headlines that do not address the nuances of planning the reduction of healthcare impact on climate change.
We are all concerned about the environmental impact of human activity on global warming and the environment. [19] Several of us are engaged in research to accelerate the introduction of low GWP therapies into the clinic, or improve our management of lung disease through appropriate device utilization. However, this communication lacks balance in its discussion, while potentially pressurizing healthcare professionals and patients inappropriately to stop or switch successful therapeutic plans. There are undoubtedly opportunities to consider the “greenest” product when patients commence therapy or alter it for reasons of poor disease control or inadequate inhaler technique.
‘Greening’ healthcare requires a more holistic assessment of the impact of inhaler choice on wider environmental metrics, as well as the consequences of possible destabilisation of patients’ conditions, and the carbon-intensiveness of the consequent extra emergency and follow-up care. While the authors correctly state that: “Key considerations for inhaler selection include healthcare professional knowledge of all the devices; inhalation manoeuvre achieved; airway disease severity, patient’s ability to use their device correctly and their personal preferences” we feel that publications such as the current report have potential to create carbon targets for prescribing in isolation from such nuanced considerations. Healthcare practitioners will welcome evidence-based approaches for identifying suitable patients and strategies for switching devices. If the burden of reducing the GWP of healthcare in the NHS is to be placed on respiratory physicians, it is essential that they have access to prescribing tools that allow appropriate stratification of product choices for patients to manage their therapeutic carbon footprint. There is no one-size-fits-all approach in respiratory care, and we believe the current Brief Communication contributes little to our ability to deliver the changes necessary to manage the environmental impact of inhalation therapies.
References
1. Janson C, Henderson R, Löfdahl M, Hedberg M, Sharma R, Wilkinson AJK. Carbon footprint impact of the choice of inhalers for asthma and COPD. Published Online First: 07 November 2019. doi: 10.1136/thoraxjnl-2019-213744
2. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019;9(10).
3. Ingraham C. No, asthma inhalers are not ‘choking the planet’. Washington Post. 2019 11 Nov 2019 https://www.washingtonpost.com/business/2019/11/11/no-asthma-inhalers-ar....
4. Levy M, Murnane D, Barnes PJ, Sanders M, Fleming L, Scullion J, et al. Inhaler devices and global warming: Flawed arguments - A Response to Wilkinson et al. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019. Available from: https://bmjopen.bmj.com/content/9/10/e028763.responses#inhaler-devices-a....
5. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. European Respiratory Journal. 2002;19(2):246-51.
6. Global Initiative for Asthma (GINA). The Global Strategy for Asthma Management and Prevention 2019. Available from: http://www.ginasthma.org.
7. Scottish Intercollegiate Guideline Network (SIGN), The British Thoracic Society British guideline on the management of asthma 2019. Available from: https://www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-a...
8. Jolliet O, Margni M, Charles R, Humbert S, Payet J, Rebitzer G, et al. IMPACT 2002+: A new life cycle impact assessment methodology. International Journal of Life Cycle Assessment. 2003;8(6):324.
9. Jeswani HK, Azapagic A. Life cycle environmental impacts of inhalers. Journal of Cleaner Production. 2019;237.
10. Trust C. Carbon Trust. GlaxoSmithKline PLC. Product Carbon Footprint Certification Summary Report 2017 (Supplementary Material to Janson et al. Thorax, 2019). Available from: https://thorax.bmj.com/content/thoraxjnl/early/2019/11/07/thoraxjnl-2019....
11. Goulet B, Olson L, Mayer BK. A comparative life cycle assessment between a metered dose inhaler and electric nebulizer. Sustainability (Switzerland). 2017;9(10).
12. National Institute for Health and Care Excellence (NICE). Asthma: diagnosis, monitoring and chronic asthma management. NICE guideline [NG80]. 2017. Available from: https://www.nice.org.uk/guidance/ng80
13. Plaza V, Giner J, Calle M, Rytilä P, Campo C, Ribó P, et al. Impact of patient satisfaction with his or her inhaler on adherence and asthma control. Allergy and Asthma Proceedings. 2018;39(6):437-44.
14. Price D, Roche N, Christian Virchow J, Burden A, Ali M, Chisholm A, et al. Device type and real-world effectiveness of asthma combination therapy: An observational study. Respiratory Medicine. 2011;105(10):1457-66.
15. Jones R, Martin J, Thomas V, Skinner D, Marshall J, d’Alcontres MS, et al. The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: A UK database study. International Journal of COPD. 2017;12:2445-54.
16. Björnsdõttir US, Gizurarson S, Sabale U. Potential negative consequences of non-consented switch of inhaled medications and devices in asthma patients. International Journal of Clinical Practice. 2013;67(9):904-10.
17. Melani AS, Paleari D. Maintaining control of chronic obstructive airway disease: Adherence to inhaled therapy and risks and benefits of switching devices. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2016;13(2):241-50.
18. Moorfields Hospital Foundation Trust. Sustainable Development Management Plan 2017 – Page 9. Available from: https://www.moorfields.nhs.uk/sites/default/files/Item%2009%20Sustainabl...
19. Usmani OS, Scullion J, Keeley D. Our planet or our patients—is the sky the limit for inhaler choice? The Lancet Respiratory Medicine. 2019;7(1):11-3.
This paper provides welcome reassurance that switching of inhalers can be carried out not only without risk of deterioration but that improvements in disease control may be seen. My supposition is that this is due to the interaction between clinician and patient to discuss the switch that stimulates increased engagement in the patient leading to better outcomes. Whatever the mechanism this paper is timely with the BBC just today featuring an article on the environmental impact of inhalers and the need to reduce the NHS carbon footprint by choosing more environmentally friendly options. https://www.bbc.co.uk/news/health-50215011
The latest BTS/SIGN national asthma guideline includes new information on this and highlights opportunities to recycle pMDIs where possible.
However, a word of caution on inhaler switching may be in order. Although only anecdotal evidence from my lengthy clinical practice I have on several occasions met patients from different surgeries who have had their regular inhaled therapies repeat prescription changed without discussion, never mind agreement - usually on cost saving rather than environmental reasons - leading at best to loss of confidence in their local surgery and at worst loss of control of their asthma such that an attack was precipitated leading to hospital admission. This was not only a significant risk for the individual but far more costly than the anticipated s...
This paper provides welcome reassurance that switching of inhalers can be carried out not only without risk of deterioration but that improvements in disease control may be seen. My supposition is that this is due to the interaction between clinician and patient to discuss the switch that stimulates increased engagement in the patient leading to better outcomes. Whatever the mechanism this paper is timely with the BBC just today featuring an article on the environmental impact of inhalers and the need to reduce the NHS carbon footprint by choosing more environmentally friendly options. https://www.bbc.co.uk/news/health-50215011
The latest BTS/SIGN national asthma guideline includes new information on this and highlights opportunities to recycle pMDIs where possible.
However, a word of caution on inhaler switching may be in order. Although only anecdotal evidence from my lengthy clinical practice I have on several occasions met patients from different surgeries who have had their regular inhaled therapies repeat prescription changed without discussion, never mind agreement - usually on cost saving rather than environmental reasons - leading at best to loss of confidence in their local surgery and at worst loss of control of their asthma such that an attack was precipitated leading to hospital admission. This was not only a significant risk for the individual but far more costly than the anticipated saving to the drug budget.
Looking to prescribe optimum inhaled therapies taking into account effectiveness, side effects, suitable technique and environmental factors amongst others must be the right thing to do and those already on treatment can clearly have that changed to a more desirable option but only with their full engagement and agreement. I hope this will not be forgotten.
I wish to congratulate the authors. I find their review on RSV-induced severe disease attractive in all respects. It impressively presents research ranging from epidemiology to molecular immunology, and includes promising treatment opportunities. My perhaps peripheral comments relate to the authors’ conclusion that “much remains to be discovered regarding the host response to RSV infection”.
Loss of epithelial cells and pathogenic roles of exaggerated epithelial regeneration.
I’d like to dwell somewhat on RSV-induced epithelial cell loss, which is mentioned in passing in the review. Bodies constituted of many epithelial cells clumped together in airway lumen material have been named Creola bodies by Naylor (1) who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread patches of epithelial shedding, may also be a prominent feature of RSV infection. Indeed, in RSV-infected infants Creola bodies in aspirates seem to be a requisite for the infection to be followed by development of asthma (2,3). This is of interest because epithelial regeneration processes alone, rather than the reputed increased permeability to inhaled material (which is not observed in vivo in asthma (4)) are causative regarding several facets of airway inflammation and remodelling (5,6).
Lethal RSV infections in children are associated with extensive and patchy loss of bron...
I wish to congratulate the authors. I find their review on RSV-induced severe disease attractive in all respects. It impressively presents research ranging from epidemiology to molecular immunology, and includes promising treatment opportunities. My perhaps peripheral comments relate to the authors’ conclusion that “much remains to be discovered regarding the host response to RSV infection”.
Loss of epithelial cells and pathogenic roles of exaggerated epithelial regeneration.
I’d like to dwell somewhat on RSV-induced epithelial cell loss, which is mentioned in passing in the review. Bodies constituted of many epithelial cells clumped together in airway lumen material have been named Creola bodies by Naylor (1) who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread patches of epithelial shedding, may also be a prominent feature of RSV infection. Indeed, in RSV-infected infants Creola bodies in aspirates seem to be a requisite for the infection to be followed by development of asthma (2,3). This is of interest because epithelial regeneration processes alone, rather than the reputed increased permeability to inhaled material (which is not observed in vivo in asthma (4)) are causative regarding several facets of airway inflammation and remodelling (5,6).
Lethal RSV infections in children are associated with extensive and patchy loss of bronchial epithelial cells as well as occurrence of a fibrinous exudate (7) that characterizes sites of epithelial regeneration (4). Exaggerated epithelial regeneration could thus qualify as a multipotent pathogenic factor in RSV-induced diseases beyond asthma. I think it would be of interest to learn about occurrence of Creola bodies and exaggerated epithelial regeneration in association with RSV infection-induced severe disease from infancy to old age.
Antimicrobial peptides and plasma exudation as first line airway defence.
The authors have included a small § on airway innate immunity aspects that could reduce or avert infections following RSV exposure. The authors specifically mention that cathelicidin, an antimicrobial peptide (AMP), could prevent RSV invasion. In accord with most features of innate immunity, local cells, which are readily studied in vitro, are generally considered sole producers of AMPs. However, in vivo in patients the situation is different. In a rare study, where the in vivo origin of induced airway surface cathelicidin was demonstrated, this AMP appeared on the airway surface exclusively as a component of plasma exudation (8). This information probably needs to be complemented with further in vivo observations in guinea-pig and human airways demonstrating that induced plasma exudation responses (eg by topical histamine challenges) produce brief and localised microvascular-epithelial exudation of non-sieved plasma. This response occurs without producing mucosal oedema, without harming the epithelium, and without increasing epithelial perviousness in the opposite direction (4).
The non-sieved and non-injurious nature of airways plasma exudation is important because cathelicidin would be accompanied by all antimicrobial proteins/peptides contained in circulating plasma (4). Also, even if AMPs occur as a result of plasma exudation, rather than being secreted by local cells, this remains a first line innate defence operating on the surface of an intact epithelial lining.
It is another matter if RSV invasion has occurred and epithelial loss is extensive – Then plasma exudation also occurs but is much more intense and of much longer duration (4). The latter response is needed to provide a suitable milieu for prompt and speedy epithelial regeneration, but if too exaggerated the effect may be detrimental to the host (4).
Carl Persson carl.persson@med.lu.se
Laboratory Medicine
University Hospital of Lund
Lund, Sweden
1. Naylor B. The shedding of the mucosa of the bronchial tree in asthma. Thorax 1962; 17:69-72.
2. Yamada Y, Yoshihara S, Arisaka O. Creola bodies in wheezing infants predict the development of asthma. Pediatr Allergy Immunol 2004; 15:159-62.
3. Yamada Y, Yoshihara S. Creola bodies in infancy with respiratory syncytial virus bronchiolitis predict the development of asthma. Allergol Int 2010; 59:375-80.
4. Persson C. Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma. J Allergy Clin Immunol 2019; 143:1271-86.
5. Persson CG, Erjefalt JS, Erjefalt I, Korsgren MC, Nilsson MC, Sundler F. Epithelial shedding--restitution as a causative process in airway inflammation. Clin Exp Allergy 1996; 26:746-55.
6. Erjefalt JS, Persson CG. Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 1997; 52:1010-2.
7. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod Pathol 2007; 20:108-19.
8. Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy 2012; 42:383-91.
We have read this vital article, and after reading we would like to agree with the findings of the authors but we would like to suggest a complementary study for future directions. The VEGF gene encodes angiogenic protein and it is located at chromosome 6p21.1. Numerous SNPs in the promoter, 5'-, and 3'- untranslated regions (UTR) VEGF have been reported. Some of the more frequent SNPs involved in major solid tumour are well reported inclusive of rs2025039 (1), rs1570360 (2), rs699947 and rs2010963 (3), rs1570360 and rs8333061 (4). There is a serious need to study the role of these SNPs in congenital diaphragmatic hernia and pulmonary hypertension.
References:
1. Krippl P, Langsenlehner U, Renner W, et al.A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. International Journal of Cancer2003;106:468–71. doi:10.1002/ijc.11238
2. Howell WM, Rose-Zerilli MJ. Cytokine Gene Polymorphisms, Cancer Susceptibility, and Prognosis. The Journal of Nutrition2007;137. doi:10.1093/jn/137.1.194s
3. Jin Q. Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis. Clinical Cancer Research2005;11:3647–53. doi:10.1158/1078-0432.ccr-04-1803
4. Gupta D, Gupta V, Singh V, et al.Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients. Meta Gene2016;9:249–53. doi:10....
We have read this vital article, and after reading we would like to agree with the findings of the authors but we would like to suggest a complementary study for future directions. The VEGF gene encodes angiogenic protein and it is located at chromosome 6p21.1. Numerous SNPs in the promoter, 5'-, and 3'- untranslated regions (UTR) VEGF have been reported. Some of the more frequent SNPs involved in major solid tumour are well reported inclusive of rs2025039 (1), rs1570360 (2), rs699947 and rs2010963 (3), rs1570360 and rs8333061 (4). There is a serious need to study the role of these SNPs in congenital diaphragmatic hernia and pulmonary hypertension.
References:
1. Krippl P, Langsenlehner U, Renner W, et al.A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. International Journal of Cancer2003;106:468–71. doi:10.1002/ijc.11238
2. Howell WM, Rose-Zerilli MJ. Cytokine Gene Polymorphisms, Cancer Susceptibility, and Prognosis. The Journal of Nutrition2007;137. doi:10.1093/jn/137.1.194s
3. Jin Q. Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis. Clinical Cancer Research2005;11:3647–53. doi:10.1158/1078-0432.ccr-04-1803
4. Gupta D, Gupta V, Singh V, et al.Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients. Meta Gene2016;9:249–53. doi:10.1016/j.mgene.2016.07.011
We read with interest this article by Dutta et al evaluating the feasibility of proton pump inhibitor (PPI) therapy in Idiopathic Pulmonary Fibrosis (IPF). We congratulate the authors for successfully conducting this first ever double blind, randomised, placebo-controlled pilot trial of PPI in IPF despite the challenges to the recruitment in this disease with high prevalence of gastroesophageal reflux. Furthermore, we agree with the authors that cough is a neglected but important outcome measure in IPF trials and they should be praised for pursuing this.
The role of gastro-oesophageal reflux in IPF has long been debated and its prevalence has been evaluated in a number of studies (1,2). However, the value of anti-acid therapy in relation to clinically meaningful outcomes has lacked true prospective randomised and controlled evaluation in previous trials/analyses. Furthermore, a pooled analysis (3) of 3 randomised controlled trials (RCTs) of Pirfenidone in IPF showed no clinical benefit of antacid use in terms of disease progression, mortality or markers of functional assessment with a signal towards increased infection rate in those with advanced disease and receiving antacids.
Though airway reflux has been implicated in the exacerbation and pathophysiology of chronic cough in IPF, the aspect of oesophageal dysmotility/ non-acid reflux has largely been ignored. Dutta and colleagues had a small fraction of patients completing oesophageal manometry in the trial (...
We read with interest this article by Dutta et al evaluating the feasibility of proton pump inhibitor (PPI) therapy in Idiopathic Pulmonary Fibrosis (IPF). We congratulate the authors for successfully conducting this first ever double blind, randomised, placebo-controlled pilot trial of PPI in IPF despite the challenges to the recruitment in this disease with high prevalence of gastroesophageal reflux. Furthermore, we agree with the authors that cough is a neglected but important outcome measure in IPF trials and they should be praised for pursuing this.
The role of gastro-oesophageal reflux in IPF has long been debated and its prevalence has been evaluated in a number of studies (1,2). However, the value of anti-acid therapy in relation to clinically meaningful outcomes has lacked true prospective randomised and controlled evaluation in previous trials/analyses. Furthermore, a pooled analysis (3) of 3 randomised controlled trials (RCTs) of Pirfenidone in IPF showed no clinical benefit of antacid use in terms of disease progression, mortality or markers of functional assessment with a signal towards increased infection rate in those with advanced disease and receiving antacids.
Though airway reflux has been implicated in the exacerbation and pathophysiology of chronic cough in IPF, the aspect of oesophageal dysmotility/ non-acid reflux has largely been ignored. Dutta and colleagues had a small fraction of patients completing oesophageal manometry in the trial (9 patients out of 45 at the baseline and 6 at the end of treatment). We propose that high resolution manometry may provide an invaluable adjunct to future larger RCTs of investigating airway reflux in IPF with the measurement of gastro-esophageal pressure gradient (4). Furthermore, Hull Airway Reflux Questionnaire (5) would be a useful adjunct to the subjective assessment incorporating the acid and non-acid reflux symptoms as a measure of airway reflux when conducting future clinical trials of either acid suppression or pro-kinetic agents in IPF.
Hence, we believe that future clinical trials of reflux in IPF should focus on non-acid reflux/ oesophageal dysmotility with a special emphasis on high resolution oesophageal manometry for comprehensive assessment of airway reflux as it is likely to be a significant contributor to chronic cough in IPF and the fact that acid suppression does not work in non-IPF chronic cough.
References:
1- Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158(6):1804-8.
2- Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE 2nd, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006 Jan;27(1):136-42.
3- Kreuter M, Wuyts W, Renzoni E, Koschel D, Maher TM, Kolb M, Weycker D, Spagnolo P, Kirchgaessler KU, Herth FJ, Costabel U. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet Respir Med. 2016;4(5):381-9. doi: 10.1016/S2213-2600(16)00067-9.
4- Burke JM, Jackson W, Morice AH. The role of high resolution oesophageal manometry in occult respiratory symptoms. Respir Med 2018: 138: 47-49.
5- Morice AH, Faruqi S, Wright CE, Thompson R, Bland JM. Cough hypersensitivity syndrome: a distinct clinical entity. Lung. 2011;189(1):73-9. doi: 10.1007/s00408-010-9272-1.
We read the extremely important paper by Crosbie et al1 with interest as it has potential implications for population screening for lung cancer. However, the paper contains some ambiguities and inconsistencies and it would be very helpful to obtain clarification from the authors in order to interpret their findings in a population screening context.
Firstly, in the methods section, it is stated that ever smokers aged 50 to 74 years registered at participating general practices were invited to a community based lung health check (LHC). It is not stated whether every individual registered as an ever smoker was invited. However, assuming this was the case it appears from the flow chart that a total of 16,402 invitation letters were sent out, but if the aim was to send these only to individuals registered as ever smokers it is not clear why 6,476 letters were sent to never smokers.
In any event, the flow chart indicates that letters were sent to 9,926 smokers and that 2,613 attended the LHC. Thus the uptake of the first filter was 26.3% which does not resonate with the first statement in the results section i.e. “Demand was extremely high”.
There are also two apparent inconsistencies in the data presented; in table 1 the number of attendees is stated as 2,541 yet in the flow chart it is 2,613. In addition, in the legend for the flow chart it is indicated that the overall numbers are based on General Practitioner recorded smoking status for 15,072 individua...
We read the extremely important paper by Crosbie et al1 with interest as it has potential implications for population screening for lung cancer. However, the paper contains some ambiguities and inconsistencies and it would be very helpful to obtain clarification from the authors in order to interpret their findings in a population screening context.
Firstly, in the methods section, it is stated that ever smokers aged 50 to 74 years registered at participating general practices were invited to a community based lung health check (LHC). It is not stated whether every individual registered as an ever smoker was invited. However, assuming this was the case it appears from the flow chart that a total of 16,402 invitation letters were sent out, but if the aim was to send these only to individuals registered as ever smokers it is not clear why 6,476 letters were sent to never smokers.
In any event, the flow chart indicates that letters were sent to 9,926 smokers and that 2,613 attended the LHC. Thus the uptake of the first filter was 26.3% which does not resonate with the first statement in the results section i.e. “Demand was extremely high”.
There are also two apparent inconsistencies in the data presented; in table 1 the number of attendees is stated as 2,541 yet in the flow chart it is 2,613. In addition, in the legend for the flow chart it is indicated that the overall numbers are based on General Practitioner recorded smoking status for 15,072 individuals and yet 16,402 letters were sent out.
With complex data like these it is easy to have small inconsistencies but it would be really helpful to have clarification of the exact method whereby potential high risk individuals were identified and invited for assessment along with precise numbers.
We should like to make a further point about the paper’s use of the term ‘false positive’. This is confined to screened individuals who are referred to the cancer clinic and who are not diagnosed with cancer. The paper reports that 2.8% of LDCT positive individuals met these criteria.
However, a larger group had indeterminate LDCT results, 12.7% in the flowchart. The majority of these had negative results on repeat CT at three months. It is debatable whether these should or should not be grouped with the false positives. However, as the flowchart helpfully shows, this group of individuals are an output of LDCT. It is worth noting here that any health decrement arising from these results should not be neglected in an evaluation of screening as a result of not being characterised as false positives.
Reference
1. Crosbie PA, Balata H, Evison M, et al. Implementing lung cancer screening: baseline results from a community-based ‘Lung Health Check’ pilot in deprived areas of Manchester. Thorax 2019;74:405–409
In the systematic review by Jolliffe et al. patients with Vitamin D deficiency benefitted most from supplementation. The hypothesis is put forward that exacerbations in the Vitamin D deficient groups are driven largely by Vitamin D deficiency. It may be that strategies aimed at reducing the prevalence of Vitamin D deficiency in the COPD population are the most effective. A population health perspective may be sensible. The Scientific Advisory Committee on Nutrition recommends a daily Vitamin D dietary intake of 10 micrograms for everyone 4 years and over. A pragmatic change to our practice could be to encourage, advocate and remind these patients to take a dietary supplement bought from their pharmacy. This advice can be imparted by clinicians during routine reviews and exacerbations both in Primary and Secondary care.
1. Jolliffe DA, Greenberg L, Hooper RL, et al, Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019;74:337-345.
2. Vitamin D and Health Report, Scientific Advisory Committee on Nutrition , 2016
We would like to thank Dr. Wingfield et al. for their thoughtful response on our cost-effectiveness analysis of tuberculosis contact tracing in London(1). The authors provide a number of insights which complement and expand upon our results and highlight the many complexities of TB interventions, both currently and as we head towards elimination.
Wingfield et al. raise important points regarding heterogeneity on contact tracing yield, something we touched upon in the discussion of our paper. As they mention, such heterogeneity is likely to increase as countries such as the UK near elimination. We found that the yield of active cases around non-pulmonary cases needed to be very high – in our analyses, the incremental cost-effectiveness ratio (ICER) for screening such contacts was below £30,000 per quality-adjusted life year (QALY) when the yield of contacts reached about 0.1 active cases found per index case, i.e. when 4% of contacts screened are positive. However, this ignores synergistic effects caused by those infectious contacts potentially being more infectious and infectious for longer, due to their being part of a high-risk group, and so the actual threshold may be lower.
We also agree with Wingfield et al. that careful thought must be given to the interpretation of the ICER in the context of TB elimination, as in any context. Rather than treating the willingness-to-pay threshold as a strict and universal cut-off value, the ICER should be considered alo...
We would like to thank Dr. Wingfield et al. for their thoughtful response on our cost-effectiveness analysis of tuberculosis contact tracing in London(1). The authors provide a number of insights which complement and expand upon our results and highlight the many complexities of TB interventions, both currently and as we head towards elimination.
Wingfield et al. raise important points regarding heterogeneity on contact tracing yield, something we touched upon in the discussion of our paper. As they mention, such heterogeneity is likely to increase as countries such as the UK near elimination. We found that the yield of active cases around non-pulmonary cases needed to be very high – in our analyses, the incremental cost-effectiveness ratio (ICER) for screening such contacts was below £30,000 per quality-adjusted life year (QALY) when the yield of contacts reached about 0.1 active cases found per index case, i.e. when 4% of contacts screened are positive. However, this ignores synergistic effects caused by those infectious contacts potentially being more infectious and infectious for longer, due to their being part of a high-risk group, and so the actual threshold may be lower.
We also agree with Wingfield et al. that careful thought must be given to the interpretation of the ICER in the context of TB elimination, as in any context. Rather than treating the willingness-to-pay threshold as a strict and universal cut-off value, the ICER should be considered alongside the whole suite of available scientific evidence and public-policy objectives, forming one component within a multi-criteria decision analysis framework featuring other considerations such as the value of international recognition of successful disease elimination(2). In this way, combined with more targeted screening programmes, it may be possible to bridge the gap between cost-effectiveness analysis and TB elimination, allowing the twain to meet.
1. Cavany SM, Vynnycky E, Anderson CS, Maguire H, Sandmann F, Thomas HL, et al. Should NICE reconsider the 2016 UK guidelines on TB contact tracing? A cost-effectiveness analysis of contact investigations in London. Thorax. 2019 Feb 1;74(2):185–93.
2. Baltussen R, Niessen L. Priority setting of health interventions: the need for multi-criteria decision analysis. Cost Eff Resour Alloc. 2006 Aug 21;4(1):14.
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.
It was with great interest and not a little concern that we read the recent Brief Communication by Janson and colleagues [1] into the impact of pressurised metered dose inhalers (pMDIs) on the global warming potential (GWP) of respiratory care. We note the tenacity of one of the authors who has succeeded in publishing a second paper [2] based on a similar, flawed logic just two weeks later. The sense of proportion that is missing in both reports has, thankfully, been identified in the press this week.[3] However, we feel it essential to scrutinise the current contribution scientifically.
The authors report the carbon footprints of a range of devices marketed by GlaxoSmithKline (GSK) following analysis undertaken by the Carbon Trust (a UK not-for dividend company). Subsequently, calculations were undertaken aimed to determine how the carbon footprint of inhalation therapy in the UK’s National Health Service (NHS) might be reduced by altering the prescribing patterns of UK physicians (where more pMDIs are prescribed than dry powder inhalers (DPIs)) to resemble those of Swedish physicians (where the converse holds). While we acknowledge the authors’ declaration that their data are potentially flawed by the fact that their calculations are based on extrapolating the carbon footprints of just three device formats manufactured by one company to predict the effects of total DPI and pMDI usage in the UK when the carbon footprints of most other devices are unknown, we wou...
Show MoreThis paper provides welcome reassurance that switching of inhalers can be carried out not only without risk of deterioration but that improvements in disease control may be seen. My supposition is that this is due to the interaction between clinician and patient to discuss the switch that stimulates increased engagement in the patient leading to better outcomes. Whatever the mechanism this paper is timely with the BBC just today featuring an article on the environmental impact of inhalers and the need to reduce the NHS carbon footprint by choosing more environmentally friendly options.
Show Morehttps://www.bbc.co.uk/news/health-50215011
The latest BTS/SIGN national asthma guideline includes new information on this and highlights opportunities to recycle pMDIs where possible.
However, a word of caution on inhaler switching may be in order. Although only anecdotal evidence from my lengthy clinical practice I have on several occasions met patients from different surgeries who have had their regular inhaled therapies repeat prescription changed without discussion, never mind agreement - usually on cost saving rather than environmental reasons - leading at best to loss of confidence in their local surgery and at worst loss of control of their asthma such that an attack was precipitated leading to hospital admission. This was not only a significant risk for the individual but far more costly than the anticipated s...
To The Editor and to The Authors.
I wish to congratulate the authors. I find their review on RSV-induced severe disease attractive in all respects. It impressively presents research ranging from epidemiology to molecular immunology, and includes promising treatment opportunities. My perhaps peripheral comments relate to the authors’ conclusion that “much remains to be discovered regarding the host response to RSV infection”.
Loss of epithelial cells and pathogenic roles of exaggerated epithelial regeneration.
I’d like to dwell somewhat on RSV-induced epithelial cell loss, which is mentioned in passing in the review. Bodies constituted of many epithelial cells clumped together in airway lumen material have been named Creola bodies by Naylor (1) who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread patches of epithelial shedding, may also be a prominent feature of RSV infection. Indeed, in RSV-infected infants Creola bodies in aspirates seem to be a requisite for the infection to be followed by development of asthma (2,3). This is of interest because epithelial regeneration processes alone, rather than the reputed increased permeability to inhaled material (which is not observed in vivo in asthma (4)) are causative regarding several facets of airway inflammation and remodelling (5,6).
Lethal RSV infections in children are associated with extensive and patchy loss of bron...
Show MoreWe have read this vital article, and after reading we would like to agree with the findings of the authors but we would like to suggest a complementary study for future directions. The VEGF gene encodes angiogenic protein and it is located at chromosome 6p21.1. Numerous SNPs in the promoter, 5'-, and 3'- untranslated regions (UTR) VEGF have been reported. Some of the more frequent SNPs involved in major solid tumour are well reported inclusive of rs2025039 (1), rs1570360 (2), rs699947 and rs2010963 (3), rs1570360 and rs8333061 (4). There is a serious need to study the role of these SNPs in congenital diaphragmatic hernia and pulmonary hypertension.
References:
1. Krippl P, Langsenlehner U, Renner W, et al.A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. International Journal of Cancer2003;106:468–71. doi:10.1002/ijc.11238
2. Howell WM, Rose-Zerilli MJ. Cytokine Gene Polymorphisms, Cancer Susceptibility, and Prognosis. The Journal of Nutrition2007;137. doi:10.1093/jn/137.1.194s
3. Jin Q. Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and Prognosis. Clinical Cancer Research2005;11:3647–53. doi:10.1158/1078-0432.ccr-04-1803
4. Gupta D, Gupta V, Singh V, et al.Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients. Meta Gene2016;9:249–53. doi:10....
Show MoreWe read with interest this article by Dutta et al evaluating the feasibility of proton pump inhibitor (PPI) therapy in Idiopathic Pulmonary Fibrosis (IPF). We congratulate the authors for successfully conducting this first ever double blind, randomised, placebo-controlled pilot trial of PPI in IPF despite the challenges to the recruitment in this disease with high prevalence of gastroesophageal reflux. Furthermore, we agree with the authors that cough is a neglected but important outcome measure in IPF trials and they should be praised for pursuing this.
Show MoreThe role of gastro-oesophageal reflux in IPF has long been debated and its prevalence has been evaluated in a number of studies (1,2). However, the value of anti-acid therapy in relation to clinically meaningful outcomes has lacked true prospective randomised and controlled evaluation in previous trials/analyses. Furthermore, a pooled analysis (3) of 3 randomised controlled trials (RCTs) of Pirfenidone in IPF showed no clinical benefit of antacid use in terms of disease progression, mortality or markers of functional assessment with a signal towards increased infection rate in those with advanced disease and receiving antacids.
Though airway reflux has been implicated in the exacerbation and pathophysiology of chronic cough in IPF, the aspect of oesophageal dysmotility/ non-acid reflux has largely been ignored. Dutta and colleagues had a small fraction of patients completing oesophageal manometry in the trial (...
We read the extremely important paper by Crosbie et al1 with interest as it has potential implications for population screening for lung cancer. However, the paper contains some ambiguities and inconsistencies and it would be very helpful to obtain clarification from the authors in order to interpret their findings in a population screening context.
Firstly, in the methods section, it is stated that ever smokers aged 50 to 74 years registered at participating general practices were invited to a community based lung health check (LHC). It is not stated whether every individual registered as an ever smoker was invited. However, assuming this was the case it appears from the flow chart that a total of 16,402 invitation letters were sent out, but if the aim was to send these only to individuals registered as ever smokers it is not clear why 6,476 letters were sent to never smokers.
In any event, the flow chart indicates that letters were sent to 9,926 smokers and that 2,613 attended the LHC. Thus the uptake of the first filter was 26.3% which does not resonate with the first statement in the results section i.e. “Demand was extremely high”.
There are also two apparent inconsistencies in the data presented; in table 1 the number of attendees is stated as 2,541 yet in the flow chart it is 2,613. In addition, in the legend for the flow chart it is indicated that the overall numbers are based on General Practitioner recorded smoking status for 15,072 individua...
Show MoreIn the systematic review by Jolliffe et al. patients with Vitamin D deficiency benefitted most from supplementation. The hypothesis is put forward that exacerbations in the Vitamin D deficient groups are driven largely by Vitamin D deficiency. It may be that strategies aimed at reducing the prevalence of Vitamin D deficiency in the COPD population are the most effective. A population health perspective may be sensible. The Scientific Advisory Committee on Nutrition recommends a daily Vitamin D dietary intake of 10 micrograms for everyone 4 years and over. A pragmatic change to our practice could be to encourage, advocate and remind these patients to take a dietary supplement bought from their pharmacy. This advice can be imparted by clinicians during routine reviews and exacerbations both in Primary and Secondary care.
1. Jolliffe DA, Greenberg L, Hooper RL, et al, Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019;74:337-345.
2. Vitamin D and Health Report, Scientific Advisory Committee on Nutrition , 2016
We would like to thank Dr. Wingfield et al. for their thoughtful response on our cost-effectiveness analysis of tuberculosis contact tracing in London(1). The authors provide a number of insights which complement and expand upon our results and highlight the many complexities of TB interventions, both currently and as we head towards elimination.
Wingfield et al. raise important points regarding heterogeneity on contact tracing yield, something we touched upon in the discussion of our paper. As they mention, such heterogeneity is likely to increase as countries such as the UK near elimination. We found that the yield of active cases around non-pulmonary cases needed to be very high – in our analyses, the incremental cost-effectiveness ratio (ICER) for screening such contacts was below £30,000 per quality-adjusted life year (QALY) when the yield of contacts reached about 0.1 active cases found per index case, i.e. when 4% of contacts screened are positive. However, this ignores synergistic effects caused by those infectious contacts potentially being more infectious and infectious for longer, due to their being part of a high-risk group, and so the actual threshold may be lower.
We also agree with Wingfield et al. that careful thought must be given to the interpretation of the ICER in the context of TB elimination, as in any context. Rather than treating the willingness-to-pay threshold as a strict and universal cut-off value, the ICER should be considered alo...
Show MoreWe 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...
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