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.
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
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.
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...
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...
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