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
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 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.
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.
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.
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.
Should lung volumes measurement accompany every spirometry?
Spyridon Fortis MD1
1Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospital and Clinics, Iowa City, IA, USA
Corresponding Author:
Spyridon Fortis, MD
UIHC – Internal Medicine
200 Hawkins Drive – C33 GH
Iowa City, IA 52242
Email: spyridon-fortis@uiowa.edu
Word Count:
Author Disclosures: Authors declare that there is no conflict of interest regarding the publication of this paper.
Running Head: Lung volumes with every spirometry
Key Words: COPD, diagnosis, lung volumes, RV/TLC, preserved lung function.
In their study published in the June 2018 issue of Thorax, Zeng et al showed that RV/TLC ratio in smokers with preserved lung function is associated with clinical diagnosis of COPD, higher rates of respiratory medications prescriptions, emergency room visits, hospitalizations, and all cause-mortality[1]. The findings strongly support that patients with respiratory symptoms and normal spirometry who have air trapping in lung volume measurements have worse outcomes than those with no air trapping. Those patients at risk for COPD may suffer early obstructive lung disease which has not yet met the spirometric criteria for COPD diagnosis.
I congratulate the authors for their study as they address a very clinically relevant topic. Further studies are neede...
Should lung volumes measurement accompany every spirometry?
Spyridon Fortis MD1
1Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospital and Clinics, Iowa City, IA, USA
Corresponding Author:
Spyridon Fortis, MD
UIHC – Internal Medicine
200 Hawkins Drive – C33 GH
Iowa City, IA 52242
Email: spyridon-fortis@uiowa.edu
Word Count:
Author Disclosures: Authors declare that there is no conflict of interest regarding the publication of this paper.
Running Head: Lung volumes with every spirometry
Key Words: COPD, diagnosis, lung volumes, RV/TLC, preserved lung function.
In their study published in the June 2018 issue of Thorax, Zeng et al showed that RV/TLC ratio in smokers with preserved lung function is associated with clinical diagnosis of COPD, higher rates of respiratory medications prescriptions, emergency room visits, hospitalizations, and all cause-mortality[1]. The findings strongly support that patients with respiratory symptoms and normal spirometry who have air trapping in lung volume measurements have worse outcomes than those with no air trapping. Those patients at risk for COPD may suffer early obstructive lung disease which has not yet met the spirometric criteria for COPD diagnosis.
I congratulate the authors for their study as they address a very clinically relevant topic. Further studies are needed to examine whether treatment of those patients improve their outcomes. The prevalence of this specific pulmonary function test pattern, though, may be much less than 30%. Using more stringent exclusion criteria, authors excluded 15,236 patients for low TLC. They also excluded 16,904 patients with interstitial lung disease to ensure that the high-risk for COPD sample is not contaminated by other lung diseases like interstitial lung disease. These numbers appear extremely high given that the prevalence of ILD is much less than 1%. The stringent exclusion criteria (120,461 of 127,940) have resulted in a very small denominator which led to overestimation of the prevalence of this PFT pattern. In previous studies, including only PFTs that met the American Thoracic Society standards from one single health system, we have shown that only 4.9% of all PFTs had TLC, RV and/or RV/TLC above the upper limit of normal[2 , 3]. Of those PFTs with normal spirometry, 12.4% of them had TLC, RV and/or RV/TLC above the upper limit of normal and 10.4% of them had RV and/or RV/TLC above the upper limit of normal[3].
Using lung volumes like RV/TLC in every day practice should be exercised with caution, in particular, in the presence of normal spirometry. The reference values determine whether a spirometric or lung volume value of an individual is normal or abnormal. Spirometric reference values are derived from large cohorts[4] while lung volume measurement values are derived from small cohort and often from samples that are not representative of our population[5]. Thus, lung volume measurements are less reliable than spirometry.
Although, lung volume measurement may offer additional prognostic information, it is still unclear whether they should be routinely performed in every patient with respiratory symptoms.
References
1. Zeng S, Tham A, Bos B, Jin J, Giang B, Arjomandi M. Lung volume indices predict morbidity in smokers with preserved spirometry. Thorax 2018 doi: 10.1136/thoraxjnl-2018-211881[published Online First: Epub Date]|.
2. Fortis S, Corazalla EO, Jacobs DR, Jr., Kim HJ. Persistent Empiric COPD Diagnosis and Treatment After Pulmonary Function Test Showed No Obstruction. Respiratory care 2016;61(9):1192-200 doi: 10.4187/respcare.04647[published Online First: Epub Date]|.
3. Fortis S, Corazalla EO, Kim HJ. Does normal spirometry rule out an obstructive or restrictive ventilatory defect? Respiratory investigation 2017;55(1):55-57 doi: 10.1016/j.resinv.2016.07.005[published Online First: Epub Date]|.
4. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. American journal of respiratory and critical care medicine 1999;159(1):179-87 doi: 10.1164/ajrccm.159.1.9712108[published Online First: Epub Date]|.
5. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. The European respiratory journal. Supplement 1993;16:5-40
We appreciate the points raised by the commentator about our study (Zeng et al.)[1] published in June 2018 issue of Thorax that (1) the prevalence of abnormal residual volume to total lung capacity ratio (RV:TLC) in our study of ever-smokers with preserved spirometry is substantially higher than that observed in the commentator’s past studies,[2-4] and (2) an assumption by the commentator that stringent exclusion of those with abnormally low TLC and those with diagnosis codes of interstitial lung diseases (ILD) in their electronic health records (EHR) may have resulted in overestimation of the prevalence of abnormally high RV:TLC among smokers with preserved spirometry.
We would like to draw the attention of commentator and readers to the following points:
1- The studies referenced by the commentator used pulmonary function tests (PFT) data collected from 708 patients in 2013 across 5 clinical sites associated with University of Minnesota Medical Center with inclusion criteria of patients 18 years of age or older with or without history of smoking.[2] They included about 50% women and 3 African Americans. Our study was performed on PFT data obtained from 1985 through 2017 through the United States Veterans Affairs (VA) nationwide EHR from 7,479 patients across 37 VA medical centers in the United States with inclusion criteria of patients 40 years of age or older with an EHR diagnosis code of smoking, which likely suggests heavy smoking for VA patients. Our st...
We appreciate the points raised by the commentator about our study (Zeng et al.)[1] published in June 2018 issue of Thorax that (1) the prevalence of abnormal residual volume to total lung capacity ratio (RV:TLC) in our study of ever-smokers with preserved spirometry is substantially higher than that observed in the commentator’s past studies,[2-4] and (2) an assumption by the commentator that stringent exclusion of those with abnormally low TLC and those with diagnosis codes of interstitial lung diseases (ILD) in their electronic health records (EHR) may have resulted in overestimation of the prevalence of abnormally high RV:TLC among smokers with preserved spirometry.
We would like to draw the attention of commentator and readers to the following points:
1- The studies referenced by the commentator used pulmonary function tests (PFT) data collected from 708 patients in 2013 across 5 clinical sites associated with University of Minnesota Medical Center with inclusion criteria of patients 18 years of age or older with or without history of smoking.[2] They included about 50% women and 3 African Americans. Our study was performed on PFT data obtained from 1985 through 2017 through the United States Veterans Affairs (VA) nationwide EHR from 7,479 patients across 37 VA medical centers in the United States with inclusion criteria of patients 40 years of age or older with an EHR diagnosis code of smoking, which likely suggests heavy smoking for VA patients. Our study included only 7.5% women but 8.8% African Americans. The populations in our study and that of the commentator’s study are very different. Given the heavier smoking burden at the VA,[5] it is not unexpected to identify higher smoking-related pathology including higher prevalence of air trapping among the VA patients. Of note, through their deployments, veterans are also exposed to high levels of air pollutants,[6] which have been shown to contribute considerably to development of chronic obstructive pulmonary disease (COPD).[7]
2- As mentioned in our article, a limitation of our study was that spirometries, and specifically full PFT, were likely done due to clinical concerns for respiratory diseases, and given the inclusion of plethysmography, the likely existence of concerns for ILD. This selection bias may then contribute to a higher prevalence of receiving an ILD diagnosis in those patients’ records in our study.
3- Abnormally low TLC could occur for reasons other than ILD including obesity, which is a common health problem and thus may have resulted in exclusions of many patients from our study.
4- It is important to note that the assumption of stringent exclusion of those with ILD and abnormally low TLC should result in the remaining included patients to have higher than expected TLC, and should not result in the remaining patients to have high RV; that is, the remaining subjects should have the same level RV but higher TLC, and hence lower RV:TLC ratio. Thus, if the commentator’s assumption that “stringent exclusion criteria resulted in a very small denominator” were correct, then the algorithm of our study indeed would have been biased towards generating lower than expected prevalence of abnormally high RV:TLC, leading to an underestimation, not overestimation, of the prevalence of abnormally high RV:TLC.
5- Most remarkably, a finding that we would like to emphasize and should not be overlooked is that regardless of whether the RV:TLC ratio was normal or abnormal, it was linearly and directly associated with respiratory morbidity and progression to spirometric COPD. No threshold level was observed.
6- It is now estimated that approximately 20% of COPD is caused by exposure to air pollutants (including pollutants other than biomass smoke such as the daily air pollution experienced by all across the globe).[8] Given above, the use of “normal” or “abnormal” values and reference equations should be approached cautiously as it is potentially extremely difficult if not impossible to develop a “normal” cohort when all earth inhabitants are being exposed to air pollutants. This is consistent with our related findings in a previous article showing that in never-smokers with history of exposure to air pollutants, all with preserved spirometry AND normal range of RV:TLC, higher RV:TLC ratio was associated with worse physiologic performance.[9]
7- Finally, the commentator’s statement about lesser reliability and lack of rationale for use of lung volumes in smokers at risk for COPD is fascinating. Spirometry is an extremely important tool in assessment of respiratory diseases including COPD. It is easier to use than plethysmography and more widely available. However, COPD is a complex disease and reducing it to one or two dimensions is unhelpful.[10] As demonstrated in our article, lung volumes, regardless of whether in the normal or abnormal range, provide an additional dimension to help prognosticate in early obstructive lung disease in those at risk for COPD. In their study of 708 patients with normal spirometry,[2] the commentator and colleagues did conclude that their “findings point out the importance of measuring lung volumes in symptomatic patients who have normal spirometry.” We fully agree with them.
References:
1. Zeng, S., et al., Lung volume indices predict morbidity in smokers with preserved spirometry. Thorax, 2018.
2. Fortis, S., E.O. Corazalla, and H.J. Kim, Does normal spirometry rule out an obstructive or restrictive ventilatory defect? Respir Investig, 2017. 55(1): p. 55-57.
3. Fortis, S., et al., The difference between slow and forced vital capacity increases with increasing body mass index: a paradoxical difference in low and normal body mass indices. Respir Care, 2015. 60(1): p. 113-8.
4. Fortis, S., et al., Persistent Empiric COPD Diagnosis and Treatment After Pulmonary Function Test Showed No Obstruction. Respir Care, 2016. 61(9): p. 1192-200.
5. Odani, S., et al., Tobacco Product Use Among Military Veterans - United States, 2010-2015. MMWR Morb Mortal Wkly Rep, 2018. 67(1): p. 7-12.
6. Falvo, M.J., et al., Airborne hazards exposure and respiratory health of Iraq and Afghanistan veterans. Epidemiol Rev, 2015. 37: p. 116-30.
7. van Koeverden, I., et al., Secondhand Tobacco Smoke and COPD Risk in Smokers: A COPDGene Study Cohort Subgroup Analysis. COPD, 2015. 12(2): p. 182-9.
8. Eisner, M.D., et al., An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2010. 182(5): p. 693-718.
9. Arjomandi, M., et al., Lung volumes identify an at-risk group in persons with prolonged secondhand tobacco smoke exposure but without overt airflow obstruction. BMJ Open Respir Res, 2018. 5(1): p. e000284.
10. Agusti, A., B. Celli, and R. Faner, What does endotyping mean for treatment in chronic obstructive pulmonary disease? Lancet, 2017. 390(10098): p. 980-987.
The National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrain...
The National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrained. Therefore, it is vital that a pragmatic approach is taken to prioritise the most cost-effective, evidence-based strategies for identifying people most at risk of latent TB infection and progression to active TB disease. Cavany et al’s excellent paper raises certain key points relating to the wider policy implications of the cost-effectiveness of TB prevention strategies in low-burden settings.
First, as set out in the World Health Organization’s “End TB Strategy”(4) and PHE and NHS England’s “Collaborative Tuberculosis Strategy 2015-2020”,(5) the shared aim of the global TB community is to eliminate tuberculosis (defined as less than one case of active TB disease per 100,000 population). This goal is especially pertinent with regards to cost-effectiveness in low burden settings like Western Europe because, as incidence and prevalence of TB continue to decline, the cost per tracing episode will increase, probably non-linearly, and therefore meeting cost-effectiveness thresholds will become increasingly difficult.(6) For example, in North West England, declines in TB incidence have been associated with an increase in the proportion of TB cases who have complex social and clinical risk factors requiring enhanced case management (ECM) and hence greater per patient resource allocation.(7)
Second, cost-effectiveness estimates often assume homogeneity of clinical and social risk factors of TB patients and contacts when, in practice, such populations are profoundly diverse. We conducted an analysis of our North West England cohort of 2,139 TB cases and their 10,019 contacts. Our research showed that prevalence of active TB disease among contacts of patients with ETB was similar to the London cohort (0.44% versus 0.7% in Cavany et al, respectively) but varies widely according to the index patient’s social and clinical complexity as measured by ECM need.(1) Excluding contacts who would meet other criteria for routine contact tracing and/or active case finding (e.g. migrants, homeless people, or drug users), the rate of active TB disease in contacts of extrapulmonary TB patients with no ECM need versus the highest ECM need were 0.06% versus 1.5%, respectively.(8) Therefore, whilst we agree that contact tracing of all ETB contacts may not be cost-effective, focusing on a small number of high-risk ETB contacts (in whom approximately 1 in 66 will have active TB disease in our North West cohort) may still be an appropriate allocation of resources in the context of aiming towards regional elimination of TB.
Third, robust cost-effectiveness analyses such as Cavany et al’s should motivate the TB community in England to evaluate the predominant drivers of the costs of their TB detection and prevention services. If existing contact tracing strategies are, as in Cavany et al’s research, shown to lack cost-effectiveness, TB multi-disciplinary teams and service providers should consider designing and implementing innovative approaches that are more efficient and better value for money. Identification and characterisation of patients’ risk of an adverse treatment outcome and contacts’ risk of a positive screening event using ECM is one simple strategy,(7,8) but there are many other potential options including: electronic or virtual screening; community engagement and outreach clinics; patient and peer-led active case finding; and socioeconomic support, incentives and enablers. It is essential that future research designing and implementing such novel strategies follows Cavany et al’s lead and includes rigorous cost-effectiveness analysis in order to best inform and guide policy makers and public health commissioners.(9)
Cavany et al’s research highlights the importance of high-quality cost-effectiveness analysis to guide TB policy. In order to provide optimal TB detection, prevention, and care services tailored to individuals, especially those in underserved groups, future TB policy decisions should take into account heterogeneity within TB populations and the inevitable decrease in cost-effectiveness of interventions in line with declining TB rates. Without such considerations, we will be unlikely to meet the goal of eliminating TB in England.
References
1) Wingfield T, MacPherson P, Cleary P, Ormerod LP. High prevalence of TB disease in contacts of adults with extrapulmonary TB. Thorax. 2018 Aug;73(8):785-787. doi: 10.1136/thoraxjnl-2017-210202. Epub 2017 Nov 16.
2) Cavany SM, Sumner T, Vynnycky E, Flach C, White RG, Thomas HL, Maguire H, Anderson C. An evaluation of tuberculosis contact investigations against national standards. Thorax. 2017 Aug;72(8):736-745. doi: 10.1136/thoraxjnl-2016-209677. Epub 2017 Apr 7.
3) McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics. 2008;26(9):733-44.
6) Smit GS, Apers L, Arrazola de Onate W, Beutels P, Dorny P, Forier AM, Janssens K, Macq J, Mak R, Schol S, Wildemeersch D, Speybroeck N, Devleesschauwer B. Cost-effectiveness of screening for active cases of tuberculosis in Flanders, Belgium. Bull World Health Organ. 2017 Jan 1;95(1):27-35. doi: 10.2471/BLT.16.169383. Epub 2016 Nov 3.
7) Tucker A, Mithoo J, Cleary P, Woodhead M, MacPherson P, Wingfield T, Davies S, Wake C, McMaster P, Bertel Squire S. Quantifying the need for enhanced case management for TB patients as part of TB cohort audit in the North West of England: a descriptive study. BMC Public Health. 2017 Nov 15;17(1):881. doi: 10.1186/s12889-017-4892-5.
8) Wingfield T, MacPherson P, Sodha P, Tucker A, Mithoo J, Squire S B, Cleary P. The association of TB patients’ social risk factors and ethnicity with prevalence of TB infection and disease among their contacts: a cohort study in North West England. Under review with International Journal of Tuberculosis and Lung Disease, August 2018.
9) Lönnroth K, Migliori GB, Abubakar I, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J. 2015 Apr;45(4):928-52. doi: 10.1183/09031936.00214014
The global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Many respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patie...
The global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Many respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patients-tourists to remain in a travel destination one month more than scheduled, launches their cost of stay and many times they are proven unable to follow this recommendation.
In our opinion, one size does not fit all. The 4-week period seems too long for a patient with pulmonary embolism severity index I or II, no evidence of right ventricular dysfunction on an imaging test, negative laboratory biomarkers on presentation (low risk patient) and a normal PaO2 on room air (4). On the other hand, the 4-week period and even more the 5-day period may be too short for a patient with pulmonary embolism severity index III-V, evidence of right ventricular dysfunction on an imaging test and positive laboratory biomarkers on presentation (intermediate high risk patient), who has a significantly higher mortality rate during the first thirty days even without traveling (4).
Thus, we believe that the risk of flying after being diagnosed with pulmonary embolism is not the same for all patients and in every case we should take into consideration the risk stratification on presentation and the PaO2 level. Further carefully designed studies taking into account risk stratification will give the answer to the tough question “should I stay or should I go” after pulmonary embolism.
References
The World Bank. Air transport, passengers carried. https://data.worldbank.org/indicator/IS.AIR.PSGR Date last accessed: December 7, 2018.
International Air Transport Association. Medical manual 11th edition. https://www.iata.org/publications/Documents/medical-manual.pdf 2018
Ahmedzai S1, Balfour-Lynn IM, Bewick T, Buchdahl R, Coker RK, Cummin AR, Gradwell DP, Howard L, Innes JA, Johnson AO, Lim E, Lim WS, McKinlay KP, Partridge MR, Popplestone M, Pozniak A, Robson A, Shovlin CL, Shrikrishna D, Simonds A, Tait P, Thomas M; British Thoracic Society Standards of Care Committee. Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax. 2011 Sep;66 Suppl 1:i1-30.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033-69, 3069a-3069k.
We read 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 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 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 MoreLommatzsch 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,
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 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 MoreShould lung volumes measurement accompany every spirometry?
Spyridon Fortis MD1
1Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospital and Clinics, Iowa City, IA, USA
Corresponding Author:
Spyridon Fortis, MD
UIHC – Internal Medicine
200 Hawkins Drive – C33 GH
Iowa City, IA 52242
Email: spyridon-fortis@uiowa.edu
Word Count:
Author Disclosures: Authors declare that there is no conflict of interest regarding the publication of this paper.
Running Head: Lung volumes with every spirometry
Key Words: COPD, diagnosis, lung volumes, RV/TLC, preserved lung function.
In their study published in the June 2018 issue of Thorax, Zeng et al showed that RV/TLC ratio in smokers with preserved lung function is associated with clinical diagnosis of COPD, higher rates of respiratory medications prescriptions, emergency room visits, hospitalizations, and all cause-mortality[1]. The findings strongly support that patients with respiratory symptoms and normal spirometry who have air trapping in lung volume measurements have worse outcomes than those with no air trapping. Those patients at risk for COPD may suffer early obstructive lung disease which has not yet met the spirometric criteria for COPD diagnosis.
Show MoreI congratulate the authors for their study as they address a very clinically relevant topic. Further studies are neede...
We appreciate the points raised by the commentator about our study (Zeng et al.)[1] published in June 2018 issue of Thorax that (1) the prevalence of abnormal residual volume to total lung capacity ratio (RV:TLC) in our study of ever-smokers with preserved spirometry is substantially higher than that observed in the commentator’s past studies,[2-4] and (2) an assumption by the commentator that stringent exclusion of those with abnormally low TLC and those with diagnosis codes of interstitial lung diseases (ILD) in their electronic health records (EHR) may have resulted in overestimation of the prevalence of abnormally high RV:TLC among smokers with preserved spirometry.
We would like to draw the attention of commentator and readers to the following points:
1- The studies referenced by the commentator used pulmonary function tests (PFT) data collected from 708 patients in 2013 across 5 clinical sites associated with University of Minnesota Medical Center with inclusion criteria of patients 18 years of age or older with or without history of smoking.[2] They included about 50% women and 3 African Americans. Our study was performed on PFT data obtained from 1985 through 2017 through the United States Veterans Affairs (VA) nationwide EHR from 7,479 patients across 37 VA medical centers in the United States with inclusion criteria of patients 40 years of age or older with an EHR diagnosis code of smoking, which likely suggests heavy smoking for VA patients. Our st...
Show MoreThe National Institute for Health and Care Excellence (NICE) 2016 Tuberculosis (TB) guidelines no longer recommend screening contacts of adults with extra-pulmonary TB (ETB). However, no new evidence since the previous published guidelines was provided to support this policy change. Moreover, despite the guidance, some regional TB multidisciplinary teams and services continue to screen ETB contacts.(1)
In their original article in Thorax, Cavany et al estimated the cost-effectiveness of screening ETB contacts in London.(2) The authors’ findings suggest that screening of such contacts is unlikely to be cost-effective at the threshold of £30,000/QALY - the “willingness to pay” threshold commonly used by NICE.(3) The authors’ findings are tempered by the data being London-specific and not generalizable to the rest of England, and the lack of robust available evidence on either transmission rates or index cases’ pre-diagnosis symptom duration. Nevertheless, the authors recognise these limitations and their sensitivity analysis suggests that, even with assumptions of higher rates of transmission or prolonged symptom duration, their principal findings would not change.
The findings of this strong, well-designed study are important and provide much needed evidence for national debate around strategies for TB contact screening. Resources for TB services across England, especially those allocated to tracing contacts of TB patients, are becoming increasingly constrain...
Show MoreThe global increase in air travel, with over 3.97 billion people traveling by air each year, and the ageing population, increase the number of those with an illness who wish to travel (1). Even more, in countries like Greece with hundreds of islands, health professionals are frequently asked to assess a patient’s fitness to fly. Doctors can receive advice and guidance mainly from two sources: the IATA passenger medical clearance guidelines (2) and the Aerospace Medical Association in which the British Thoracic Society’s recommendations for air travel (3) are suggested.
Show MoreMany respiratory conditions can affect a passenger’s fitness to fly with pulmonary embolism being the most debatable (3). A major question that respiratory physicians frequently have to answer, mostly with visitors from overseas who need to be repatriated following diagnosis of pulmonary embolism, is about the right time to “fly with a clot”. The British Thoracic Society guidelines recommend against airline travel during the first four weeks following pulmonary embolism (3). On the other hand, in the IATA medical guidelines published in 2018 it is suggested that patients can fly 5 days after an acute pulmonary embolism episode, if they receive anticoagulation and their PaO2 is normal on room air (2). Although there is little scientific evidence to support the above mentioned recommendations, the huge difference in the suggested period can really confuse healthcare professionals. Moreover, asking patie...
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