Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Although inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivatio...
Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Although inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivation of smoking cessation, such as lower nicotine dependency4, older age,4 5 6 higher socioeconomic group,5 being married,5 and higher education.7 Therefore, the integrated smoking cessation interventions should be considered besides CT lung screening.
In summary, the study performed by Kate Brain and colleagues provides important new data regarding the effect of CT lung cancer screening for high-risk smokers. It also sheds light on the issue that smoking cessation needs multi-disciplinary counseling in combination with pharmacotherapy8. Here, we would like to emphasize that the impact of lung CT screening on the motivation of active smokers is a double-edged sword. The positive CT scan results could bring a higher motivation of smoking cessation, whereas the negative and the indeterminate results might actually decrease the motivation, or even let smokers give up the smoking cessation. For high-risk active smokers without positive CT screening results, specific medical consultation and more support are needed as soon as possible.
A quit rate of 21% in controls and 24% in screened persons show that CT screening is a poor motivation to quit. The authors emphasize that the quit rate was 30% in patients with a positive result on CT who needed additional clinical investigation, however, the quit rate was only 15% in persons receiving a negative CT result. This shows that CT screening lowers the motivation to quit if a negative result (expected for the majority) nourishes misperceptions. Zeliadt et al. ( JAMA Intern Med 2015; 175:1530-7) found that in 49% these beliefs were reinforced and potentially exacerbated by screening and lowered the motivation to participate in smoking cessation programs. Therefore CT screening for lung cancer without accompanying smoking cessation program could be harmful.
We read with great interest the article by Wright et al (1) published recently on the Thorax. We congratulate the authors for the study that focused on an important issue, an optimal dose of mobilization in critically ill patients. This is a very well designed clinical trial that allows us to delve deeper into discussions about training load variables applied to critical patients.
The authors named the main study training load variable of intensity. However we note that the duration of the program was the main difference between the groups and not the intensity. This is, because duration is the time period for a specific activity, while the intensity is relative to the rate of energy expenditure required to perform the activity (aerobic activity) or the magnitude of the force exerted during the resistance exercise (2).
It was unclear how muscle strength training progressed and there was no measure of energy expenditure (even if indirectly with accelerometers or perceived exertion scales), so we can not clearly state that there was a difference in the intensity of the groups, even though they had a longer duration for the intervention group (3). It is well known that in healthy subjects, shorter duration and shorter intervals may have substantially higher energy expenditure and may affect the metabolic pathways differently (4). A reality that still deserves more attention in intensive care mobilization studies.
We read with great interest the article by Wright et al (1) published recently on the Thorax. We congratulate the authors for the study that focused on an important issue, an optimal dose of mobilization in critically ill patients. This is a very well designed clinical trial that allows us to delve deeper into discussions about training load variables applied to critical patients.
The authors named the main study training load variable of intensity. However we note that the duration of the program was the main difference between the groups and not the intensity. This is, because duration is the time period for a specific activity, while the intensity is relative to the rate of energy expenditure required to perform the activity (aerobic activity) or the magnitude of the force exerted during the resistance exercise (2).
It was unclear how muscle strength training progressed and there was no measure of energy expenditure (even if indirectly with accelerometers or perceived exertion scales), so we can not clearly state that there was a difference in the intensity of the groups, even though they had a longer duration for the intervention group (3). It is well known that in healthy subjects, shorter duration and shorter intervals may have substantially higher energy expenditure and may affect the metabolic pathways differently (4). A reality that still deserves more attention in intensive care mobilization studies.
References
1. Wright SE, Thomas K, Watson G, et al. Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial. Thorax. 2017.
2. American College of Sports Medicine. ACSM's guidelines for exercise testing and prescription. Lippincott Williams & Wilkins. 2013.
3. Beach LJ, Fetterplace K, Edbrooke L, et al. Measurement of physical activity levels in the Intensive Care Unit and functional outcomes: An observational study. Journal of Critical Care. 2017;40: 89-196.
4. Tabata I. et al. Effects of moderate-intensity endurance and high-intensity intermittent training on anaerobic capacity and VO2max. Medicine and science in sports and exercise. 1996;28:1327-1330.
I read with great interest the article “The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia”, by Brownell and colleagues [1]. The study has great methodological strength, and I applaud the authors for such an elegant work. But what really caught my attention was the clear use of pre-test probability and likelihood ratio to establish the diagnosis of usual interstitial pneumonia (UIP) in patients with suspected UIP. I believe this article should change the way we care for those patients.
The study included patients with “possible UIP" and “inconsistent with UIP” patterns on high-resolution computed tomography (HRCT) of the chest. Those patients represent a diagnostic dilemma we commonly face in interstitial lung diseases clinical practice. Three different radiologists (two in the derivation and one in the validation cohort) reviewed the HRCT scans, and most importantly: they were blinded to clinical information and pathology results. All patients had the reference standard surgical lung biopsy, which were prospectively evaluated by expert pathologists.
The likelihood ratio for male patients, with ≥ 60 years-old, and possible UIP with traction bronchiectasis score ≥ 4 was as high as 47 in the derivation cohort. Since likelihood ratios are a ratio of two likelihoods (the likelihood of a test results in disease / the likelihood of the same test result in no disease [2]), the further away from on...
I read with great interest the article “The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia”, by Brownell and colleagues [1]. The study has great methodological strength, and I applaud the authors for such an elegant work. But what really caught my attention was the clear use of pre-test probability and likelihood ratio to establish the diagnosis of usual interstitial pneumonia (UIP) in patients with suspected UIP. I believe this article should change the way we care for those patients.
The study included patients with “possible UIP" and “inconsistent with UIP” patterns on high-resolution computed tomography (HRCT) of the chest. Those patients represent a diagnostic dilemma we commonly face in interstitial lung diseases clinical practice. Three different radiologists (two in the derivation and one in the validation cohort) reviewed the HRCT scans, and most importantly: they were blinded to clinical information and pathology results. All patients had the reference standard surgical lung biopsy, which were prospectively evaluated by expert pathologists.
The likelihood ratio for male patients, with ≥ 60 years-old, and possible UIP with traction bronchiectasis score ≥ 4 was as high as 47 in the derivation cohort. Since likelihood ratios are a ratio of two likelihoods (the likelihood of a test results in disease / the likelihood of the same test result in no disease [2]), the further away from one the better. So, what a likelihood of 47 means is that male patients with ≥ 60 years-old and possible UIP with traction bronchiectasis score ≥ 4 are 47 times more likely to have UIP versus not have UIP. This would move us from a pretest probability of IPF of 60% to a post-test probability of IPF of 98% in the derivation cohort, for example.
How to translate that into clinical practice? We have to start with an estimation of the pre-test probability of UIP in our patients. For that, it would have been helpful if the authors had used the variables gender and age to stratify the pre-test probability, similarly to the pre-test probability stratification we do in the evaluation for pulmonary embolism (with the Well’s criteria [3]) and lung cancer (with the Mayo Clinic prediction rule [4]). Then, we could apply the likelihood ratios of the HRCT findings to reach a post-test probability. It would be useful to know the likelihood ratio of a possible UIP with traction bronchiectasis score ≥ 4 encountered in the present study.
In conclusion, we will probably continue to struggle to make an accurate diagnosis of UIP in our patients with suspected UIP. But at least, this study allows us to struggle with some good data in our hands.
References
[1] Brownell R, Moua T, Henry TS, et al. The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax. 2017;72:424–429.
[2] Richardson WS, Wilson MC, Keitz SA, et al. Tips for Teachers of Evidence-based Medicine : Making Sense of Diagnostic Test Results Using Likelihood Ratios When to Use This Tip When to Use This Tip. J Gen Intern Med. 2007;23:87–92.
[3] Chunilal SD, Simel DL. Does This Patient Have Pulmonary Embolism ? JAMA J. Am. Med. Assoc. 2014;290:2849–2858.
[4] Swensen SJ, Silverstein MD, Edell ES, et al. Solitary pulmonary nodules : Clinical prediction model versus physicians. Mayo Cllinic Proc. 1999;74:319–329.
Magnetic resonance imaging (MRI) of the lung is an exciting field that is currently undergoing a period of rapid advancement. With its ability to measure lung function as well as structure, MRI stands to greatly improve our understanding of cystic fibrosis (CF) pathophysiology in children. However, there are still a number of significant hurdles to overcome if MRI is to become a tool for routine monitoring of paediatric CF lung disease.
Compared to other commonly used modalities such as computed tomography (CT), spirometry, and multiple breath washout (MBW), MRI is considerably more expensive and, due to high demand, generally has long wait times for access. In addition, the cost of Helium for inhalation as a contrast agent is substantial, and due to diminishing reserves, access is likely to be more problematic in the future. The use of hyperpolarised gas requires expensive equipment that is not available in all centres, such as specially tuned radiofrequency coils and a gas hyperpolariser, as well as the expertise to run them [1]. The significant cost to set up and maintain such a system presents a huge barrier to entry for many CF centres, compared to the nearly universal presence of CT and lung function testing facilities.
Standardisation of MRI between centres is challenging. Many sequences are protected under intellectual property law resulting in vendor-specific protocols, hampering comparisons between platforms [2]. Magnetic field inhomogeneity can lea...
Magnetic resonance imaging (MRI) of the lung is an exciting field that is currently undergoing a period of rapid advancement. With its ability to measure lung function as well as structure, MRI stands to greatly improve our understanding of cystic fibrosis (CF) pathophysiology in children. However, there are still a number of significant hurdles to overcome if MRI is to become a tool for routine monitoring of paediatric CF lung disease.
Compared to other commonly used modalities such as computed tomography (CT), spirometry, and multiple breath washout (MBW), MRI is considerably more expensive and, due to high demand, generally has long wait times for access. In addition, the cost of Helium for inhalation as a contrast agent is substantial, and due to diminishing reserves, access is likely to be more problematic in the future. The use of hyperpolarised gas requires expensive equipment that is not available in all centres, such as specially tuned radiofrequency coils and a gas hyperpolariser, as well as the expertise to run them [1]. The significant cost to set up and maintain such a system presents a huge barrier to entry for many CF centres, compared to the nearly universal presence of CT and lung function testing facilities.
Standardisation of MRI between centres is challenging. Many sequences are protected under intellectual property law resulting in vendor-specific protocols, hampering comparisons between platforms [2]. Magnetic field inhomogeneity can lead to variability between individual scanners, even of the same model/manufacturer [3]. In comparison, the SCI-FI project has demonstrated that image quality standardisation of CT is feasible, facilitating collaborative studies and longitudinal lung disease monitoring [4].
Finally, due to long imaging times, the need for the patient to remain still, and loud noises generated by the scanner, lung MRI is challenging to perform in children under six years unless sedation is used. As a result, the sensitivity of MRI to detect early CF-related lung disease in these young children has not yet been established. In contrast, with the advent of high-pitch, rapid acquisition techniques, CT can be performed in infants and young children without the need for sedation and with minimal motion artefact [5], with a high sensitivity [6, 7].
Radiation-free lung imaging is an attractive prospect for monitoring respiratory disease in children with CF. However, it is important to recognise that the risks from CT, if any, are extremely small [8, 9], especially in the era of ultra-low dose CT imaging [5]. The long-term risks of, for example, sedation or Xenon inhalation, are not well characterised and have not undergone such scrutiny as medical radiation.
In summary, lung MRI is a promising research tool that has an important role to play in understanding and treating CF lung disease. However, there are still many challenges that need to be overcome before MRI becomes a routine clinical tool for monitoring lung disease in children with CF.
1. Kauczor H-U, Surkau R, Roberts T. MRI using hyperpolarized noble gases. Eur Radiol 1998: 8(5): 820-827.
2. Biederer J, Beer M, Hirsch W, Wild J, Fabel M, Puderbach M, Van Beek EJ. MRI of the lung (2/3). Why ... when ... how? Insights Imaging 2012: 3(4): 355-371.
3. Vovk U, Pernus F, Likar B. A review of methods for correction of intensity inhomogeneity in MRI. IEEE transactions on medical imaging 2007: 26(3): 405-421.
4. Kuo W, Kemner-van de Corput MPC, Perez-Rovira A, de Bruijne M, Fajac I, Tiddens HAWM, van Straten M. Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis: the way forward. European Respiratory Journal 2016: 47(6): 1706-1717.
5. Lell MM, May M, Deak P, Alibek S, Kuefner M, Kuettner A, Kohler H, Achenbach S, Uder M, Radkow T. High-pitch spiral computed tomography: effect on image quality and radiation dose in pediatric chest computed tomography. Investigative radiology 2011: 46(2): 116-123.
6. Ramsey KA, Rosenow T, Turkovic L, Skoric B, Banton G, Adams AM, Simpson SJ, Murray C, Ranganathan SC, Stick SM, Hall GL, Cf A. Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis. American journal of respiratory and critical care medicine 2016: 193(1): 60-67.
7. Rosenow T, Oudraad MCJ, Murray CP, Turkovic L, Kuo W, de Bruijne M, Ranganathan SC, Tiddens HAWM, Stick SM, Fibrosis ARESTfC. PRAGMA-CF A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis. American journal of respiratory and critical care medicine 2015: 191(10): 1158-1165.
8. Kuo W, Ciet P, Tiddens HA, Zhang W, Guillerman RP, van Straten M. Monitoring cystic fibrosis lung disease by computed tomography. Radiation risk in perspective. American journal of respiratory and critical care medicine 2014: 189(11): 1328-1336.
9. Rosenow T, Oudraad MCJ, Murray CP, Turkovic L, Kuo W, de Bruijne M, Ranganathan SC, Tiddens HAWM, Stick SM. Reply: Excess Risk of Cancer from Computed Tomography Scan Is Small but Not So Low as to Be Incalculable. American journal of respiratory and critical care medicine 2015: 192(11): 1397-1399.
The paper by Yoon et al [1] addressees an important subject - diabetes mellitus (DM) probably increases the risk of TB by a factor of three [2]. The authors present data showing an association of poorer diabetes control status with both the characteristics of pulmonary TB at presentation, and the response to treatment. Compared to patients with no or controlled DM, those with uncontrolled DM reported worse symptoms at presentation, were more likely to be sputum smear positive, and had more substantial radiographic changes. Patients with uncontrolled DM were also more likely to remain sputum culture positive at two months, and either fail treatment or die.
Although these observations are entirely consistent with a biologically plausible explanation that hyperglycaemia itself influences the development of TB and its response to treatment, there is an important confounding factor which may not have been fully accounted for: treatment adherence, and the wider general use of health care.
Patients with uncontrolled diabetes, by definition, are less well treated than those with controlled diabetes. Part of the reason for this will be treatment adherence. Such patients may also be less well engaged with health services. Hence a reason for more advanced TB disease at diagnosis in those with uncontrolled DM compared to controlled or no DM might be due to later presentation to health services. Indeed, a recent study in China reported that patients with hyperglycaemia a...
The paper by Yoon et al [1] addressees an important subject - diabetes mellitus (DM) probably increases the risk of TB by a factor of three [2]. The authors present data showing an association of poorer diabetes control status with both the characteristics of pulmonary TB at presentation, and the response to treatment. Compared to patients with no or controlled DM, those with uncontrolled DM reported worse symptoms at presentation, were more likely to be sputum smear positive, and had more substantial radiographic changes. Patients with uncontrolled DM were also more likely to remain sputum culture positive at two months, and either fail treatment or die.
Although these observations are entirely consistent with a biologically plausible explanation that hyperglycaemia itself influences the development of TB and its response to treatment, there is an important confounding factor which may not have been fully accounted for: treatment adherence, and the wider general use of health care.
Patients with uncontrolled diabetes, by definition, are less well treated than those with controlled diabetes. Part of the reason for this will be treatment adherence. Such patients may also be less well engaged with health services. Hence a reason for more advanced TB disease at diagnosis in those with uncontrolled DM compared to controlled or no DM might be due to later presentation to health services. Indeed, a recent study in China reported that patients with hyperglycaemia are more likely to delay presenting to health services with symptoms of pulmonary TB [3].
And at least part of the reason for delayed sputum culture conversion in uncontrolled DM in the current study could be poorer adherence to TB treatment. Although this was not entirely borne out by the data, there was a suggestion of poorer treatment compliance in patients who remained culture positive at two months compared to those who did not (Table 3; p=0.22). It is not clear from the paper how TB treatment compliance was associated with DM control status. Neither is it clear precisely what methods were employed by the TB nurse in the study to assess treatment adherence.
So although the findings of Yoon et al support a direct effect of diabetes control status on TB presentation and treatment response, further work is required to exclude the potential confounding effects of delayed presentation of TB and adherence to treatment. Health records could be used to assess level of engagement with health services prior to the TB diagnosis, and directly-observed TB treatment in all study subjects could address potential compliance issues.
References:
1. Yoon YS, Jung JW, Jeon EJ et al. The effect of diabetes control status on treatment response in pulmonary tuberculosis: A prospective study. Thorax. 2017; 72: 263–70.
2. Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: A systematic review of 13 observational studies. PLoS Med. 2008; 5: e152.
3. Wang Q, Ma A, Han X et al. Hyperglycemia is associated with increased risk of patient delay in pulmonary tuberculosis in rural areas. J Diabetes. 2017; 9: 648–655.
I have read the paper by McDowell et al with great interest. While the trial showed no significant improvement in the main outcome measure it is crucial to understand why. The intervention group had 30 patients who were recruited from 6 hospitals over a period of 3 years or in other words hospitals recruited 1-2 patients per year who had personalised (lonely) exercise sessions. Outcomes from rehabilitation of COPD are thought to be driven by a multi-disciplinary approach [1] and peer-support from fellow patients [2]. The latter is likely to improve resilience [3] and impact on overall self-reported quality of life.
[1] Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet. 2000 Jan 29;355(9201):362-8.
[2] Poureslami I, Camp P, Shum J, Afshar R, Tang T, FitzGerald JM. Using Exploratory Focus Groups to Inform the Development of a Peer-Supported Pulmonary Rehabilitation Program: DIRECTIONS FOR FURTHER RESEARCH. J Cardiopulm Rehabil Prev. 2017 Jan;37(1):57-64.
[3] Bradley-Roberts EM, Subbe CP. Role of Psychological Resilience on Health-Outcomes in Hospitalized Patients with Acute Illness: A Scoping Review. Acute Med. 2017;16(1):10-15.
We are grateful to the authors for their comments on the PEARL paper, especially those supporting our decision to assess outcome over 90 days. In regard to CODEX, most, but not all, patients had been hospitalised and, more importantly, death or readmission was not the primary outcome.1 Developed tools tend to be optimal for their primary outcome; a tool specifically designed to predict readmission/ death without readmission is likely to be a better predictor of this outcome than one that was not developed primarily for this purpose. This may, at least in part, explain the observed difference in performance. Prognostic tools should also undergo external validation. However, we acknowledge that the brevity of the abstract makes this unclear. At the editor’s discretion, we suggest the abstract could be amended to state: “no tool has been developed and externally validated…”
We agree that data about mortality alone is relevant, and highlight that this is included in table E3 in the online supplement. The optimal predictors of death and readmission are not identical, although there is overlap. The reasons for including readmission or death without readmission as a combined outcome are: 1) they are competing risks, and assessing readmission alone would mean that death without readmission would be categorised as a favourable outcome; 2) a patient who would otherwise have died at home may be readmitted if they are identified as high risk and appropriate services are put in...
We are grateful to the authors for their comments on the PEARL paper, especially those supporting our decision to assess outcome over 90 days. In regard to CODEX, most, but not all, patients had been hospitalised and, more importantly, death or readmission was not the primary outcome.1 Developed tools tend to be optimal for their primary outcome; a tool specifically designed to predict readmission/ death without readmission is likely to be a better predictor of this outcome than one that was not developed primarily for this purpose. This may, at least in part, explain the observed difference in performance. Prognostic tools should also undergo external validation. However, we acknowledge that the brevity of the abstract makes this unclear. At the editor’s discretion, we suggest the abstract could be amended to state: “no tool has been developed and externally validated…”
We agree that data about mortality alone is relevant, and highlight that this is included in table E3 in the online supplement. The optimal predictors of death and readmission are not identical, although there is overlap. The reasons for including readmission or death without readmission as a combined outcome are: 1) they are competing risks, and assessing readmission alone would mean that death without readmission would be categorised as a favourable outcome; 2) a patient who would otherwise have died at home may be readmitted if they are identified as high risk and appropriate services are put in place; and 3) hospital admission may prevent death. One way to analyse readmissions alone without including death as a favourable outcome would be to exclude those that died. However, this would bias the population by excluding those at higher risk of readmission. We plan to separately publish data on long-term predictors of death.
We acknowledge the difficulties diagnosing heart failure with preserved ejection fraction, previously termed diastolic heart failure, and its prevalence in this population. However, this does not carry the same mortality risk as left ventricular dysfunction. We separately assessed heart failure as a clinical diagnosis alone (without the need for evidence of reduced left ventricular function on echocardiography); this did not have the same predictive power as left ventricular failure. Consequently, left ventricular failure based on echocardiogram results was appropriately selected. We also highlight the European Society of Cardiology position: “Echocardiography is the most useful, widely available test in patients with suspected HF to establish the diagnosis.”2
The Charlson Index comprises of 19 indices and is a component of CODEX and LACE. The PEARL index includes only two measures of co-morbidity (individually shown to be strong predictors of outcome), and was superior to LACE in all three cohorts, and to CODEX in two of three cohorts. It is clear that the PEARL score is more parsimonious than scores containing the Charlson index, and therefore it is easier to score. Furthermore, it can be recalled and calculated at the bedside. Whilst we agree that ideally a full medical history should be performed in all patients, the more indices that appear in a score, the more likely that there will be missing data leading to biased estimates.
1. Almagro P, Soriano JB, Cabrera FJ, et al. Short- and medium-term prognosis in patients hospitalized for COPD exacerbation: the CODEX index. Chest 2014; 145(5): 972-80.
2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18(8): 891-975.
We read with great interest the recent study by Negatu et al. which illustrated significantly increased risks for respiratory troubles such as chronic cough and breath shortness and decreased lung functions in farm workers exposed to pesticide as compared to unexposed workers 1. However, the authors have not controlled for farming practices of both exposed and unexposed groups; did they use diesel-powered or gasoline-powered vehicles to plow their fields? Diesel exhaust may exacerbate, in particular, allergic airway inflammation 2 and thus could account for increased risk of adverse respiratory health. Also, pesticide could contribute to asthma exacerbation 3. Therefore, there might existed synergistic effects of pesticide and diesel exhaust particles on impaired respiratory health in exposed subjects as compared to unexposed ones (in particular, office workers) in their studies, which raise the possibility to exaggerate the results.
We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of AL...
We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of ALI, used very widely by investigators in ALI research including ourselves2-5. Dr Zhang stated that large doses of LPS often result in release of apoptotic bodies but few MVs from alveolar macrophages, but we wonder if this statement is based on in vitro experiments using non-primary cells, rather than in vivo ALI models? Dr Zhang’s group recently showed6 the production of apoptotic bodies with 1µg LPS treatment, but their results were obtained using an immortalised cell line (MH-S alveolar macrophages) in vitro, rather than primary alveolar macrophages in vivo. Interestingly, they observed that apoptotic body production peaked later (at 6 hours) when primary cells (bone marrow derived macrophages) were treated with LPS in vitro, highlighting a clear difference between primary cells and immortalised cell lines (such as RAW cells, THP-1 and MH-S cells)6. While we cannot entirely exclude the possibility that some apoptotic bodies were produced within our model, it has been shown that i.t. LPS in vivo does not initiate apoptosis of alveolar macrophages until much later time points7,8. Taken together, we believe that concerns regarding apoptotic bodies influencing our conclusions are unsubstantiated for the acute responses investigated in our model. This is of course not to say that the release of apoptotic bodies or other EVs does not play an important role during subsequent phases of ALI pathophysiology.
Sanooj Soni, Michael R Wilson, Kieran P O’Dea, Masao Takata
Section of Anaesthetics, Pain Medicine & Intensive Care, Imperial College London, UK
1. Soni S, Wilson MR, O'dea KP, et al. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax 2016;71(11):1020-29.
2. Woods SJ, Waite AA, O'Dea KP, et al. Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation. American Journal of Physiology-Lung Cellular and Molecular Physiology 2015;308(9):L912-L21.
3. Gong J, Wu Zy, Qi H, et al. Maresin 1 mitigates LPS‐induced acute lung injury in mice. British journal of pharmacology 2014;171(14):3539-50.
4. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature medicine 2012;18(5):759-65.
5. Dorr AD, Wilson MR, Wakabayashi K, et al. Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies. Journal of Applied Physiology 2011;111(1):177-84.
6. Zhu Z, Zhang D, Lee H, et al. Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. Journal of Leukocyte Biology 2017:jlb. 3A1116-483R.
7. Vernooy JH, Dentener MA, Van Suylen RJ, et al. Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-α and infiltrating neutrophils. American journal of respiratory cell and molecular biology 2001;24(5):569-76.
8. Kearns MT, Barthel L, Bednarek JM, et al. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation. American Journal of Physiology-Lung Cellular and Molecular Physiology 2014;307(1):L62-L70.
Recently, Kate Brain and colleagues1 reported in the Thorax a randomized controlled trial concerning the favorable effect of CT lung cancer screening on the smoking cessation motivation. The study proved that implementation of a lung cancer screening program offered opportunities of smoking cessation for high risk smokers. Furthermore, this trial suggested that CT lung screening should be integrated into the smoking cessation interventions.
Show MoreAlthough inspiring, the study was not specifically designed to test the effect of lung screening on smokers who received negative screening results. Lacking the comparison between negative and positive ones, we should be cautious in drawing the final conclusion with the findings only from those with positive results of CT scan.
As we all known, results of CT screening include three categories, namely positive, negative and indeterminate. There has been increasing evidence suggesting that CT lung screening may offer a ‘license to smoke’ for active smokers who have negative results2. For those with indeterminate results, the trend towards increased smoking cessation was not significant though3. In fact, a large number of heavy smokers have no sign of lung cancer in the CT scan in clinical practice, which might make these smokers feel more comfortable to continue smoking. Thus, more attention should be paid to those without positive scanning results. there are several demographic predictors of increased likelihood and motivatio...
A quit rate of 21% in controls and 24% in screened persons show that CT screening is a poor motivation to quit. The authors emphasize that the quit rate was 30% in patients with a positive result on CT who needed additional clinical investigation, however, the quit rate was only 15% in persons receiving a negative CT result. This shows that CT screening lowers the motivation to quit if a negative result (expected for the majority) nourishes misperceptions. Zeliadt et al. ( JAMA Intern Med 2015; 175:1530-7) found that in 49% these beliefs were reinforced and potentially exacerbated by screening and lowered the motivation to participate in smoking cessation programs. Therefore CT screening for lung cancer without accompanying smoking cessation program could be harmful.
We read with great interest the article by Wright et al (1) published recently on the Thorax. We congratulate the authors for the study that focused on an important issue, an optimal dose of mobilization in critically ill patients. This is a very well designed clinical trial that allows us to delve deeper into discussions about training load variables applied to critical patients.
The authors named the main study training load variable of intensity. However we note that the duration of the program was the main difference between the groups and not the intensity. This is, because duration is the time period for a specific activity, while the intensity is relative to the rate of energy expenditure required to perform the activity (aerobic activity) or the magnitude of the force exerted during the resistance exercise (2).
It was unclear how muscle strength training progressed and there was no measure of energy expenditure (even if indirectly with accelerometers or perceived exertion scales), so we can not clearly state that there was a difference in the intensity of the groups, even though they had a longer duration for the intervention group (3). It is well known that in healthy subjects, shorter duration and shorter intervals may have substantially higher energy expenditure and may affect the metabolic pathways differently (4). A reality that still deserves more attention in intensive care mobilization studies.
References
1. Wright SE, Thomas K, Wa...
Show MoreI read with great interest the article “The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia”, by Brownell and colleagues [1]. The study has great methodological strength, and I applaud the authors for such an elegant work. But what really caught my attention was the clear use of pre-test probability and likelihood ratio to establish the diagnosis of usual interstitial pneumonia (UIP) in patients with suspected UIP. I believe this article should change the way we care for those patients.
The study included patients with “possible UIP" and “inconsistent with UIP” patterns on high-resolution computed tomography (HRCT) of the chest. Those patients represent a diagnostic dilemma we commonly face in interstitial lung diseases clinical practice. Three different radiologists (two in the derivation and one in the validation cohort) reviewed the HRCT scans, and most importantly: they were blinded to clinical information and pathology results. All patients had the reference standard surgical lung biopsy, which were prospectively evaluated by expert pathologists.
The likelihood ratio for male patients, with ≥ 60 years-old, and possible UIP with traction bronchiectasis score ≥ 4 was as high as 47 in the derivation cohort. Since likelihood ratios are a ratio of two likelihoods (the likelihood of a test results in disease / the likelihood of the same test result in no disease [2]), the further away from on...
Show MoreMagnetic resonance imaging (MRI) of the lung is an exciting field that is currently undergoing a period of rapid advancement. With its ability to measure lung function as well as structure, MRI stands to greatly improve our understanding of cystic fibrosis (CF) pathophysiology in children. However, there are still a number of significant hurdles to overcome if MRI is to become a tool for routine monitoring of paediatric CF lung disease.
Compared to other commonly used modalities such as computed tomography (CT), spirometry, and multiple breath washout (MBW), MRI is considerably more expensive and, due to high demand, generally has long wait times for access. In addition, the cost of Helium for inhalation as a contrast agent is substantial, and due to diminishing reserves, access is likely to be more problematic in the future. The use of hyperpolarised gas requires expensive equipment that is not available in all centres, such as specially tuned radiofrequency coils and a gas hyperpolariser, as well as the expertise to run them [1]. The significant cost to set up and maintain such a system presents a huge barrier to entry for many CF centres, compared to the nearly universal presence of CT and lung function testing facilities.
Standardisation of MRI between centres is challenging. Many sequences are protected under intellectual property law resulting in vendor-specific protocols, hampering comparisons between platforms [2]. Magnetic field inhomogeneity can lea...
Show MoreThe paper by Yoon et al [1] addressees an important subject - diabetes mellitus (DM) probably increases the risk of TB by a factor of three [2]. The authors present data showing an association of poorer diabetes control status with both the characteristics of pulmonary TB at presentation, and the response to treatment. Compared to patients with no or controlled DM, those with uncontrolled DM reported worse symptoms at presentation, were more likely to be sputum smear positive, and had more substantial radiographic changes. Patients with uncontrolled DM were also more likely to remain sputum culture positive at two months, and either fail treatment or die.
Although these observations are entirely consistent with a biologically plausible explanation that hyperglycaemia itself influences the development of TB and its response to treatment, there is an important confounding factor which may not have been fully accounted for: treatment adherence, and the wider general use of health care.
Patients with uncontrolled diabetes, by definition, are less well treated than those with controlled diabetes. Part of the reason for this will be treatment adherence. Such patients may also be less well engaged with health services. Hence a reason for more advanced TB disease at diagnosis in those with uncontrolled DM compared to controlled or no DM might be due to later presentation to health services. Indeed, a recent study in China reported that patients with hyperglycaemia a...
Show MoreI have read the paper by McDowell et al with great interest. While the trial showed no significant improvement in the main outcome measure it is crucial to understand why. The intervention group had 30 patients who were recruited from 6 hospitals over a period of 3 years or in other words hospitals recruited 1-2 patients per year who had personalised (lonely) exercise sessions. Outcomes from rehabilitation of COPD are thought to be driven by a multi-disciplinary approach [1] and peer-support from fellow patients [2]. The latter is likely to improve resilience [3] and impact on overall self-reported quality of life.
[1] Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet. 2000 Jan 29;355(9201):362-8.
[2] Poureslami I, Camp P, Shum J, Afshar R, Tang T, FitzGerald JM. Using Exploratory Focus Groups to Inform the Development of a Peer-Supported Pulmonary Rehabilitation Program: DIRECTIONS FOR FURTHER RESEARCH. J Cardiopulm Rehabil Prev. 2017 Jan;37(1):57-64.
[3] Bradley-Roberts EM, Subbe CP. Role of Psychological Resilience on Health-Outcomes in Hospitalized Patients with Acute Illness: A Scoping Review. Acute Med. 2017;16(1):10-15.
We are grateful to the authors for their comments on the PEARL paper, especially those supporting our decision to assess outcome over 90 days. In regard to CODEX, most, but not all, patients had been hospitalised and, more importantly, death or readmission was not the primary outcome.1 Developed tools tend to be optimal for their primary outcome; a tool specifically designed to predict readmission/ death without readmission is likely to be a better predictor of this outcome than one that was not developed primarily for this purpose. This may, at least in part, explain the observed difference in performance. Prognostic tools should also undergo external validation. However, we acknowledge that the brevity of the abstract makes this unclear. At the editor’s discretion, we suggest the abstract could be amended to state: “no tool has been developed and externally validated…”
We agree that data about mortality alone is relevant, and highlight that this is included in table E3 in the online supplement. The optimal predictors of death and readmission are not identical, although there is overlap. The reasons for including readmission or death without readmission as a combined outcome are: 1) they are competing risks, and assessing readmission alone would mean that death without readmission would be categorised as a favourable outcome; 2) a patient who would otherwise have died at home may be readmitted if they are identified as high risk and appropriate services are put in...
Show MoreWe read with great interest the recent study by Negatu et al. which illustrated significantly increased risks for respiratory troubles such as chronic cough and breath shortness and decreased lung functions in farm workers exposed to pesticide as compared to unexposed workers 1. However, the authors have not controlled for farming practices of both exposed and unexposed groups; did they use diesel-powered or gasoline-powered vehicles to plow their fields? Diesel exhaust may exacerbate, in particular, allergic airway inflammation 2 and thus could account for increased risk of adverse respiratory health. Also, pesticide could contribute to asthma exacerbation 3. Therefore, there might existed synergistic effects of pesticide and diesel exhaust particles on impaired respiratory health in exposed subjects as compared to unexposed ones (in particular, office workers) in their studies, which raise the possibility to exaggerate the results.
Dear Editors
We thank Dr Zhang and colleagues for their comments on our paper1. We certainly agree that in this emerging field of extracellular vesicle (EV) research, it is vital that identification and characterisation of different EV populations are as robust as possible. To this end, we very much welcome detailed discussions on methodologies used for each study, to enhance and improve the quality of EV-related work within the lung research community.
In our paper, we specifically chose to examine the role of microvesicles (MVs) in acute lung injury (ALI), and the roles of apoptotic bodies and exosomes are beyond the scope of the study. We do not exclude the presence of apoptotic bodies or surfactant micelles in our in vivo samples, or indeed single or clustered MVs larger than 1µm, however our surface marker analysis of MV subpopulations by flow cytometry was deliberately conservative and limited to only events below the conventional size cut off of 1µm. Hence figure 3 of our paper shows effectively only one EV population, i.e. MVs. For our isolation of MVs for functional studies, we used differential centrifugation to enrich MVs but these technical matters were discussed in some detail in the published manuscript.
Dr Zhang and colleagues have concerns about the dose of LPS (20µg) used in our in vivo ALI model. However, intratracheal (i.t.) instillation of high dose LPS (20µg or more per mouse) is a clinically-relevant, well established model of AL...
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