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We thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of mon...
We thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of monitoring for the individual with subsequent avoidance of alarm fatigue.
1. Hodgson LE, Dimitrov BD, Congleton J, Venn R, Forni LG, Roderick PJ. A validation of the National Early Warning Score to predict outcome in patients with COPD exacerbation. Thorax 2017;72(1):23-30 doi: 10.1136/thoraxjnl-2016-208436.
2. Prytherch DR, Smith GB, Schmidt PE, Featherstone PI. ViEWS--Towards a national early warning score for detecting adult inpatient deterioration. Resuscitation 2010;81(8):932-7 doi: 10.1016/j.resuscitation.2010.04.014.
Dear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry t...
Dear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry the very minimal amount of popular microRNAs (miRNAs). Even for those most promising miRNA markers, less than 1 copy of miRNA can be found in each Exo[5]. This is part of the reason why the classification of EVs may be important.
In the work presented by Dr. Soni et al, a very large dose of LPS (20 μg per mouse) has been delivered to mice via intratracheal instillation. Certainly, different batch of LPS may carry different levels of potency. However, we found that the larger dose of LPS often quickly resulted in the release of ABs but rather than MVs by alveolar macrophages. In our experiences, as little as 1 μg LPS (Sigma-Aldrich, cat #L2630, St. Louis, MO, USA) resulted in the robust amount of MVs (about 50% in total EVs). However, a fair amount of Exos (about 25% in total EVs) is still mixed in the LPS-induced EVs. Additionally, the FACS analysis presented in figure 3 shows only one population of vesicles. This could be due to the overly too large dose of LPS and the detected EVs fall mainly on the range of ABs. In our experience, using a smaller dose of LPS, we often clearly observe two different population of EVs, one belongs to the larger size of ABs, and the other belongs to the smaller MVs.
We recognize that the variability of results could result from different technique, detecting apparatus, different batch of LPS and also different size/age/strain of mice. However, we would like to discuss our findings on this emerging novel topic and our comments may be found interesting and useful by other audience.
Thank you for your time and attention!
REFERENCES
1. Soni S, Wilson MR, O'Dea KP, et al. Alveolar macrophage-derived microvesicles mediate acute lung injury. Thorax 2016;71(11):1020-29. doi: 10.1136/thoraxjnl-2015-208032
2. Gyorgy B, Szabo TG, Pasztoi M, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011;68(16):2667-88. doi: 10.1007/s00018-011-0689-3
3. Yanez-Mo M, Siljander PRM, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015;4 doi: ARTN 27066
10.3402/jev.v4.27066
4. Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 2013;200(4):373-83. doi: 10.1083/jcb.201211138
5. Alexander M, Hu RZ, Runtsch MC, et al. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun 2015;6 doi: ARTN 7321
10.1038/ncomms8321
I enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencie...
I enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencies undermines the attraction of using EWS: consistency. If each patient has an individualised plan, often dependent on which individual healthcare professional has seen them, the consistency of response is lost. An on-call team member told of a score that has been individually put together cannot know what the urgency of response required is compared to a standardised score. Whilst there will be extreme cases where individualised plans are required, the population of patients with target oxygen saturations of 88-92%, make up a large enough proportion of the inpatient population to justify a standardised alternative score to suit their needs during the middle and latter portions of their admission. I would propose that NEWS is used at the “front door” for all patients to enable early senior review for these patients, but that once a senior clinical decision maker has prescribed target oxygen saturations of 88-92%, a standardised score for patients at risk of type 2 respiratory failure is a better method of monitoring these patients subsequently.
We read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%...
We read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%), clinicians would need to adjust the scoring parameters for almost half of patients with AECOPD to avoid repeated un-necessary “callouts”. Since there is no evidence-based system for making such adjustments, it may be worth considering the extension of the Salford-NEWS system to most patients with AECOPD as an interim solution.
This study does, however, demonstrate that the Salford-NEWS system, when applied blindly to all admitted patients with AECOPD (at risk of hypercapnia or not); at a score threshold of >5, generated fewer “alarms” requiring clinical callouts compared with the NEWS system, (the percent reduction is not revealed in the paper) but at the same time maintaining comparable positive and negative predicted values. Our previously published data, reported a “callout” rate of 56% for patients deemed to be at risk of hypercapnia when NEWS was used compared with 18% using the Salford-NEWS system.3 Such high “callout” rate would very quickly lead to “alarm fatigue”, as described by the authors, particularly at a time when hospital rotas are extremely pressurised. We note that similar concerns over NEWS and its tendency to trigger an increased volume of alerts in patients with AECOPD were raised by the authors in 2013. 4
Therefore, we would be concerned over the clinical appropriateness of keeping the NEWS score unadjusted for COPD patients, as suggested by Hodgson and colleagues, when the callout rate is as high as 44% with no evidence of improved outcomes in this cohort, particularly on reducing mortality through better and earlier identification of clinical deterioration leading to step-up in care; which can only be tested in a prospectively designed study. That said, the effort made by the investigators to extract evidence on such an important subject using retrospective data has to be applauded.
Furthermore, as it is known that the risk of death in AECOPD may be at least doubled if too much oxygen is given, 5, 6 we would argue strongly that bedside observation systems should help clinicians to identify patients with iatrogenic hyperoxaemia as well as identifying hypoxaemia. In addition to mortality benefit, evidence on COPD admission bundles demonstrates that when oxygen target ranges are assessed and documented correctly within 1 hour of admission, the mean length of stay is significantly reduced (LOS <5 days; OR 1.84(1.38-2.46)).6 Thus, in promoting more accurate assessments of oxygen target ranges, Salford-NEWS can be viewed as a better care-lower cost model of quality improvement.
The NEWS and CREWS systems do not flag hyperoxaemia although there are increasing safety concerns about this, not just in hypercapnic patients but also in a variety of medical conditions including myocardial infarction where Nehme et al. have reported an increase in infarct size of 17-21% associated with the unnecessary use of supplemental oxygen.7 Apart from patients at risk of hypercapnia, the Salford-NEWS system allocates one point for iatrogenic hyperoxaemia (target saturation is 94-98%, but patient is on Oxygen with measured saturation >98%) prompting nursing staff to titrate down un-necessary Oxygen. Bedside charts should not just predict risk of death but should also guide and facilitate best practice including the avoidance of hyperoxaemia, especially in oxygen sensitive patients.
References
1. Hodgson LE, Dimitrov BD, Congleton j et al . A validation of the National Early Warning Score to predict outcomes in patients with COPD exacerbation. Thorax 2016 In press
2. O’Driscoll BR, Bakerly ND, Murphy P et al. Concerns regarding the design of the bedside monitoring chart for use with the NEWS (National Early Warning System). Clinical Medicine 2013: 13:319-320
3. O’Driscoll BR, Grant K, Green D et al. Clinical and scientific letters: The national early warning score gives misleading scores for oxygen saturation in patients at risk of hypercapnia. Clinical Medicine 2014;14:695–696
4. Hodgson L, Bax S, Montefort M et al. The National Early Warning Score (NEWS) and iatrogenic harm – Could the NEWS for COPD patients be improved. Thorax. 2013;68:A37
5. Austin MA, Wills KE, Blizzard L, et al Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ. 2010 Oct 18;341:c5462
6. Turner AM, Lim WS, Rodrigo C, et al. A care-bundles approach to improving standard of care in AECOPD admissions: results of a national project. Thorax. 2015 Oct;70(10):992-4.
7. Nehme Z, Stub D, Bernard S, et al. AVOID Investigators. Effect of supplemental oxygen exposure on myocardial injury in ST-elevation myocardial infarction. Heart. 2016 ;102:444-51
Dear Editor, We thank Dr Mansell for her comments regarding our
recently published trial. [1] We agree that there are different phenotypic
variations within the obesity hypoventilation syndrome (OHS), although it
remains to be determined whether OHS with co-existent obstructive sleep
apnoea (OSA) responds differently to treatment in comparison to OHS
without OSA. [2] Acknowledging that the presence and severity of OSA in...
Dear Editor, We thank Dr Mansell for her comments regarding our
recently published trial. [1] We agree that there are different phenotypic
variations within the obesity hypoventilation syndrome (OHS), although it
remains to be determined whether OHS with co-existent obstructive sleep
apnoea (OSA) responds differently to treatment in comparison to OHS
without OSA. [2] Acknowledging that the presence and severity of OSA in
OHS may impact on the response to CPAP or non-invasive ventilation (NIV),
clinical definitions and clinical trials in OHS have defined OHS as
obesity (BMI > 30 kg/m2) with chronic hypercapnia, irrespective of the
degree of co-existent OSA. [3] The degree of OSA in our study is in
keeping with the severity of OSA in previous clinical trial of OHS, [4,
5], although the degree of obesity, severity of baseline hypercapnia and
degree of pulmonary function impairment was substantially greater. All
three randomised controlled trials have found similar outcomes for CPAP
and NIV, and so do not support the routine use of NIV for all patients
with OHS. The predominant phenotype appears to be OHS in conjunction with
severe OSA, which comprised more than 70% of participants in the recent
manuscript from the Spanish Sleep Network. [6] In this subgroup they found
NIV provided greater improvement in respiratory failure and symptoms than
life style measure in OHS without OSA, however further results are awaited
to determine whether CPAP and NIV have different impacts in this subgroup.
We chose clinically significant outcomes and predictors of increased
mortality (hospital admission, persisting respiratory failure, non-
adherence and quality of life) as outcome measures rather than
polysomnographic variables. We did, however, use polysomnography to
titrate CPAP and NIV at the commencement of the project in order to
eliminate respiratory events and minimise persisting hypoxaemia and
hypoventilation. In terms of demonstrating laboratory effectiveness of
therapy, none of the participants required the addition of nocturnal
oxygen for persisting hypoxaemia on treatment, in contrast to other
trials, although we did not measure the apnoea hypopnoea index on the
final study settings. [5] We agree that assessment of long term outcomes,
including mortality is important and 12 month outcome data from this
cohort will be available shortly.
Some of the participants in our trial had treatment prior to trial
randomisation. The trial recruited OHS participants during acute hospital
admissions with respiratory failure as well as from ambulatory settings
that were the focus of previous trials. The design allowed for initial
treatment with NIV for correction of acute respiratory acidosis prior to
randomisation to CPAP or NIV. We acknowledge that this may have
influenced baseline measures, however it was not considered ethical to
withhold treatment in acutely unwell patients and there was no difference
in prior treatment use between the groups. Given the results from the
three published randomised controlled trials that have found similar
outcomes for CPAP and NIV in OHS, and in line with recent editorial
opinion, we believe that it is reasonable to use CPAP for treatment of OHS
following initial stabilisation of acute respiratory acidosis, with
careful observation of the response. [7], Further evidence may influence
optimal therapy in different OHS subgroups.
1.Howard ME, Piper AJ, Stevens B, et al. A randomised controlled trial of
CPAP versus non-invasive ventilation for initial treatment of obesity
hypoventilation syndrome. Thorax. 2016. Epub 2016/11/18.
2.Ojeda Castillejo
E, de Lucas Ramos P, Lopez Martin S, et al. Noninvasive mechanical ventilation in patients with obesity hypoventilation syndrome. Long-term outcome and prognostic factors. Arch Bronconeumol. 2015;51(2):61-8. Epub 2014/04/08.
3.Mokhlesi B, Tulaimat A. Recent Advances in Obesity
Hypoventilation Syndrome. Chest.2007;132(4):1322-36.
4.Piper AJ, Wang D, Yee BJ, et al. Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal
desaturation. Thorax. 2008;63(5):395-401. Epub 2008/01/22.
5.Masa JF,
Corral J, Alonso ML, et al. Efficacy of Different Treatment Alternatives
for Obesity Hypoventilation Syndrome. Pickwick Study. Am J Respir Crit
Care Med. 2015;192(1):86-95. Epub 2015/04/29.
6.Masa JF, Corral J,
Caballero C, et al. Non-invasive ventilation in obesity hypoventilation
syndrome without severe obstructive sleep apnoea. Thorax. 2016;71(10):899-
906. Epub 2016/07/14.
7.Noda JR, Masa JF, Mokhlesi B. CPAP or non-invasive
ventilation in obesity hypoventilation syndrome: does it matter which one
you start with? Thorax. 2017. Epub 2017/01/29.
Conflict of Interest:
MEH reports grants from Resmed Foundatio & non-financial support from Philips Respironics. AJP reports grants from Resmed Foundation, personal fees from ResMed, personal fees from Philips Respironics & personal fees from SenTec. DM reports grants from Resmed Foundation, National Health & Medical Research Council & Victoria Neurotrauma Initiative. BS, AEH, BJY, ED, ATB, DF, CB, LR, NS, DH and DJB report a grant from Resmed Foundation.
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is in...
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is increasing data to suggest the clinical entity of obesity related respiratory failure (ORRF) encompasses several different phenotypes including; hypercapnic OSA, OSA/OHS and lone OHS. The underlying pathophysiology is likely to differ between these phenotypes and will therefore respond differently to treatment[2]. Not all the participants underwent nocturnal respiratory polygraphy, and it is thus difficult to determine which clinical phenotype was being treated, especially given the wide standard deviation (for AHI mean = 82 events / hr (SD 45) and for SpO2 less than 90% mean = 67% of the sleep period (SD 31.4%). This is in keeping with data by Kawata et al[3], who also demonstrated that in patients with hypercapnic OSA, only half of patients responded to continuous positive airway pressure (CPAP) therapy. Those who failed to respond had a higher AHI and BMI, suggesting nocturnal polygraphy parameters may predict who will respond to CPAP therapy alone. More than 50% of patients had previously used either non-invasive ventilation (NIV) or CPAP therapy, it is unclear whether there was a wash out period and prior use of PAP therapy which may have affected compliance in these individuals and therefore outcomes. We note the mean CPAP was 15.2 cm H2O (SD 2.8); in our clinical experience we often find patients with OHS/OSA trialled on CPAP therapy who require higher CPAP pressures (>10cmH2O) have ongoing nocturnal events, particularly persistent hypoxia. The authors have not provided nocturnal data on PAP therapy, we are therefore unable to determine whether the CPAP group had a reduction in nocturnal events to within normal range. This is especially important given the fact that, although reduced, the PaCO2 in the CPAP group remained higher than the NIV group at three months. The authors also comment that PaCO2 at presentation was predictive of treatment failure, with an eightfold increase in risk when PaCO2 was greater than 62mmHg (8.27kPa). This is noteworthy since there is much debate about the diagnostic criteria for OHS[4-6], a cut-off level for PaCO2 to determine which patients may fail therapy would be clinically important in identifying patients who should be treated with NIV in the first instance. Lastly, only outcomes at 3 months have been presented. We wonder what the longer term outcomes for these patients would be; whether there would be an increase in the CPAP failure rate and, most importantly, a difference in mortality rates? We recognise the significance of this paper and acknowledge there may be a cohort of OHS/hypercapnic OSA patients who can be treated successfully with CPAP. However, this group is yet to be identified; much of this distinction may lie in a universal definition of OHS encompassing nocturnal and daytime parameters. We suggest that NIV is a safer treatment option until further phenotyping studies are conducted to comprehensively identify those patients requiring NIV and those for whom CPAP will be adequate.
References:
1. Howard ME, Piper AJ, Stevens B, et al. A randomised controlled trial of CPAP versus non-invasive ventilation for initial treatment of obesity hypoventilation syndrome. Thorax 2016 doi: 10.1136/thoraxjnl-2016-208559[published Online First: Epub Date]|.
2. Masa JF, Corral J, Caballero C, et al. Non-invasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnoea. Thorax 2016:thoraxjnl-2016-208501
3. Kawata N, Tatsumi K, Terada J, et al. DAytime hypercapnia in obstructive sleep apnea syndrome*. Chest 2007;132(6):1832-38 doi: 10.1378/chest.07-0673[published Online First: Epub Date]|.
4. Manuel AR, Hart N, Stradling JR. Is a raised bicarbonate, without hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation? CHEST Journal 2015;147(2):362-68
5. Murphy PB, Janssens J-P. NIV for OHS without severe OSAS: is it worth it? Thorax 2016 doi: 10.1136/thoraxjnl-2016-208986[published Online First: Epub Date]|.
6. Hart N, Mandal S, Manuel A, et al. Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax 2014;69(1):83-4 doi: 10.1136/thoraxjnl-2013-204298[published Online First: Epub Date]|.
We thank Professors Lipworth and Anderson for their very thoughtful
comments in their response to our piece1, and for pointing out clear
strategies for treating obesity-associated asthma without expensive
therapies, e.g., with improved delivery of inhaled corticosteroids and/or
weight reduction.
It should be noted however, that the focus of the piece was on
mechanisms by which obesity might cause asthma,...
We thank Professors Lipworth and Anderson for their very thoughtful
comments in their response to our piece1, and for pointing out clear
strategies for treating obesity-associated asthma without expensive
therapies, e.g., with improved delivery of inhaled corticosteroids and/or
weight reduction.
It should be noted however, that the focus of the piece was on
mechanisms by which obesity might cause asthma, with the idea that a
greater understanding of disease mechanisms causing obesity-associated
asthma might lead to improved therapies, and possibly to even cost
effective ones. From a pathogenesis point of view, even pilot studies
showing the efficacy of any therapy might be extremely valuable in
identifying specific molecular mechanisms of disease. In that regard, the
impetus of the article was that obesity-associated asthma represents a
significant and growing unmet medical need, characterized by increased
healthcare utilization and reduced quality of life, and refractory to even
oral corticosteroid treatment and other current therapies. These current
therapies include inhaled corticosteroids and weight reduction programs,
although improved delivery or compliance with these measures, as suggested
by Professors Lipworth and Anderson, could improve the clinical result.
It is also worth mentioning that studies of obesity-associated
asthma, as mentioned in the piece1, indicate that there are at least two
forms of the disease, an early onset form and a late onset form, one of
which is much more responsive to weight reduction (late onset form) than
the other. We would therefore advocate further study of disease
mechanisms causing asthma in obese individuals, including subpopulations
thereof, along with improved implementation of current inexpensive
treatments, that might lead to an improved understanding and possibly to
new therapies for this very significant, growing and costly public heath
problem.
1. Umetsu, D.T. Mechanisms by which obesity impacts asthma. Thorax
(2016).
We read with interest the state of the art review by Umetsu on
mechanisms by which obesity impacts asthma [1]. He has clearly outlined
the extent to which molecular targets, both within allergic (T-helper 2
[TH2]) and non-allergic mechanistic pathways of asthma, need further
evaluation and drug development for obese asthmatics. This was on the
basis that current standard therapies for asthma such as inhaled
corticoste...
We read with interest the state of the art review by Umetsu on
mechanisms by which obesity impacts asthma [1]. He has clearly outlined
the extent to which molecular targets, both within allergic (T-helper 2
[TH2]) and non-allergic mechanistic pathways of asthma, need further
evaluation and drug development for obese asthmatics. This was on the
basis that current standard therapies for asthma such as inhaled
corticosteroids (ICS) appear to be less effective in these individuals.
Whilst these novel molecular targets are clearly an exciting step forward,
we believe there are several other issues that need to be addressed as
well when it comes to standard asthma treatment with ICS in the obese.
Umetsu touched on altered lung mechanics in the obese stating more
restriction of lung volumes[2]. We have found previously that overweight asthmatics (body mass index [BMI]???25kg/m2) appear to have attenuated
fractional exhaled nitric oxide (FeNO) and symptom responses as the dose
of inhaled budesonide was increased up to 800?g/day compared to normal
weight (BMI<25kg/m2) counterparts receiving the same ICS dose ramp[3].
However, there were no differences seen between responses in airway
calibre as measured by forced expiratory volume in 1s (FEV1), or indeed
airway hyperresponsiveness (AHR) to methacholine. Therefore, altered
corticosteroid response at a molecular level alone does not necessarily
explain the equal response in these latter two outcomes. Certainly, in
significantly overweight individuals their lung volumes are reduced, but
we did not see this difference in our cohort, presumably reflecting a
modestly increased mean BMI of 30kg/m2.
It may be, therefore, that either the ICS is not being delivered to the
peripheral small airways sufficiently in obese asthmatics, in the presence
of normal proximal delivery[4]. A previous study examined the effects of
bariatric surgery on measures of peripheral small airway function and
asthma between asthmatic and non-asthmatic obese individuals finding that
the peripheral airways are more collapsible in obese asthmatics than in
their non-asthmatic counterparts[5]. Indeed small airway dysfunction
itself is associated with poorer asthma control[6 7], which could feasibly
have a greater impact in obese asthmatics.
Therefore, strategies to improve delivery of ICS to the peripheral airways
might be a more cost-effective first step for certain obese asthmatics
than going directly to more expensive biological therapies to improve
their asthma control. We believe further prospective study is required
into the lung distribution and clinical utility of extra-fine particle ICS
in obese asthmatics, as well to establish if higher than usual doses of
ICS are required to achieve the same effect as in normal weight
asthmatics. It goes without saying that strategies which target
significant weight loss - including bariatric surgery where necessary -
are likely to be even more cost-effective in the first place, as this will
not only impact on improving asthma control but also on comorbidities such
as diabetes and hypertension.
References
1. Umetsu DT. Mechanisms by which obesity impacts asthma. Thorax 2016.
2. King GG, Brown NJ, Diba C, et al. The effects of body weight on airway calibre. Eur Respir J 2005;25(5):896-901.
3. Anderson WJ, Lipworth BJ. Does body mass index influence responsiveness to inhaled corticosteroids in persistent asthma? Ann Allergy Asthma Immunol 2012;108(4):237-42.
4. Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. The Lancet Respiratory medicine 2014;2(6):497-506.
5. Al-Alwan A, Bates JH, Chapman DG, et al. The nonallergic asthma of obesity. A matter of distal lung compliance. Am J Respir Crit Care Med 2014;189(12):1494-502.
6. Manoharan A, Anderson WJ, Lipworth J, et al. Small airway dysfunction is associated with poorer asthma control. Eur Respir J 2014;44(5):1353-5.
7. Shi Y, Aledia AS, Tatavoosian AV, et al. Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol 2012;129(3):671-8.
We thank Dr. Lacasse and the HP Study Group for their correspondence
regarding 'A diagnostic model for chronic hypersensitivity pneumonitis',
and appreciate their thoughtful consideration of our work.(1) We agree
that these two studies are complementary, and hope that both will serve to
improve diagnostic accuracy in the evaluation of patients with suspected
HP. We further concur that much work remains to be done to advan...
We thank Dr. Lacasse and the HP Study Group for their correspondence
regarding 'A diagnostic model for chronic hypersensitivity pneumonitis',
and appreciate their thoughtful consideration of our work.(1) We agree
that these two studies are complementary, and hope that both will serve to
improve diagnostic accuracy in the evaluation of patients with suspected
HP. We further concur that much work remains to be done to advance our
understanding of HP.
The HP Study was a pivotal paper in our field, the first to define a
clinically applicable prediction model to diagnose acute, subacute and
chronic HP.(2) However, the HP Study cohort included patients with
'active' disease, specifically excluding patients with fibrotic sequelae
or 'residual inactive HP'. Notably, an inciting antigen was identified in
114/116 (97%) of patients with HP. Our focus was on a different clinical
population and conundrum - the differentiation of chronic, commonly
fibrotic HP from other fibrotic interstitial lung diseases, in particular
idiopathic pulmonary fibrosis (IPF). These HP patients typically do not
present with an acute pulmonary syndrome, and previous data from our
center have demonstrated 60% to be antigen indeterminate, despite thorough
investigation,(3) consistent with data from similar sub-specialty
centers.(4) We required surgical lung biopsy as part of our gold standard
multi-disciplinary discussion-based diagnosis of HP given the lack of
universally accepted non-histopathological criteria in this clinical
scenario.
The study of HP is challenging, attributable to a lack of universally
accepted diagnostic criteria, the conundrum of antigen indeterminate
disease and controversies over the clinical utility of bronchoalveolar
lavage fluid analysis, serum specific antibodies, and inhalational
challenge. A recent review suggests focused areas for future research and
we are enthused by the increasing interest in this area.(5) Along with the
HP Study group, we remain hopeful that our complementary contributions to
clinical prediction models will lead to an overall better diagnostic
accuracy of HP in all its forms, and ultimately improved patient care.
Kerri A. Johannson MD MPH, University of Calgary, Calgary AB Canada;
Brett M. Elicker MD, University of California, San Francisco, San
Francisco CA USA;
Eric Vittinghoff PhD, University of California, San Francisco, San
Francisco CA USA;
Deborah Assayag MD, McGill University, Montreal QC Canada;
Kaissa de Boer MD, University of Ottawa, Ottawa ON Canada;
Jeffrey A. Golden MD, University of California, San Francisco, San
Francisco CA USA;
Kirk D. Jones MD, University of California, San Francisco, San Francisco
CA USA;
Talmadge E. King Jr. MD, University of California, San Francisco, San
Francisco CA USA;
Laura L. Koth MD, University of California, San Francisco, San Francisco
CA USA;
Joyce S. Lee MD, University of Colorado, Denver, Aurora CO USA;
Brett Ley MD, University of California, San Francisco, San Francisco CA
USA;
Paul J. Wolters MD, University of California, San Francisco, San Francisco
CA USA;
Harold R. Collard MD, University of California, San Francisco, San
Francisco CA USA.
References
1. Johannson KA, Elicker BM, Vittinghoff E, Assayag D, de Boer K,
Golden JA, Jones KD, King TE, Koth LL, Lee JS, Ley B, Wolters PJ, Collard
HR. A diagnostic model for chronic hypersensitivity pneumonitis. Thorax
2016.
2. Lacasse Y, Selman M, Costabel U, Dalphin JC, Ando M, Morell F,
Erkinjuntti-Pekkanen R, Muller N, Colby TV, Schuyler M, Cormier Y.
Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care
Med 2003; 168: 952-958.
4. Fernandez Perez ER, Swigris JJ, Forssen AV, Tourin O, Solomon JJ, Huie
TJ, Olson AL, Brown KK. Identifying an inciting antigen is associated with
improved survival in patients with chronic hypersensitivity pneumonitis.
Chest 2013; 144: 1644-1651.
5. Salisbury ML, Myers JL, Belloli EA, Kazerooni EA, Martinez FJ, Flaherty
KR. Diagnosis and Treatment of Fibrotic Hypersensitivity Pneumonia. Where
We Stand and Where We Need to Go. Am J Respir Crit Care Med 2016.
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and
often relies on an array of clinical symptoms and signs developed in an
appropriate setting, with the demonstration of radiographic and
tomographic abnormalities, serum precipitating antibodies against
offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage,
and/or a granulomatous reaction on lung biopsies. Taken...
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and
often relies on an array of clinical symptoms and signs developed in an
appropriate setting, with the demonstration of radiographic and
tomographic abnormalities, serum precipitating antibodies against
offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage,
and/or a granulomatous reaction on lung biopsies. Taken separately, all
these manifestations are nonspecific and only the combination of several
of them may help clinicians to arrive at a correct diagnosis. By
providing better estimates of the probability of a disease than clinical
judgement, prediction rules (i.e., tools that quantifies the contribution
that various components of the history, physical examination and basic
laboratory results makes toward the diagnosis in an individual patient)
may guide clinical practice.[1] In this regard, we read with much
interest Johannson and colleagues' report of a multidimensional diagnostic
model for chronic hypersensitivity pneumonitis (HP).[2] This research
parallels the HP Study previously reported, the objective of which was to
develop a clinical prediction rule for the diagnosis of active HP.[3]
Johannson's study bears some resemblance to the HP study, especially
in its statistical methods. However, similarities end here. The HP study
was a prospective multicenter study of 661 patients presenting with an
acute pulmonary syndrome for which HP was considered in the differential
diagnosis. Johannson's study is a single-center retrospective analysis of
190 patients with biopsy-proven, chronic HP. The HP study specifically
applied to active acute, subacute and chronic HP, and only excluded
inactive residual HP. It included consecutive patients, chosen in an
unbiased fashion and representing a wide spectrum of diseases from a
variety of institutions, hence increasing generalizability. By including
only patients who required surgical lung biopsy, Johannson and colleagues
likely preselected difficult cases of HP and non-HP interstitial lung
disease, with the consequence of underestimating the accuracy of their
prediction models. The HP Study looked at simple and objective clinical
criteria and used high resolution computed tomography (HRCT) in the gold
standard definition of HP, whereas Johansson's study incorporated
radiological features from HRCT and a radiologist's diagnostic impression
in their prediction model. Bronchoalveolar lavage was obtained in all
patients in the HP study but it was not considered in Johannson's study.
Johannson's study and the HP Study are not competing studies; they
are complementary and their results cannot be directly compared. Although
the two studies had different patient populations and case selection, they
may be useful in the appropriate setting. Both studies have another point
in common: to be elevated in the hierarchy of evidence for clinical
decision rules, they should be validated again in different
populations.[1]
Yves Lacasse MD, Institut universitaire de cardiologie et de
pneumologie de Quebec, Universite Laval, Quebec, Canada
Moises Selman MD, Instituto Nacional de Enfermedades Respiratorias,
Mexico DF, Mexico
1 McGinn TG, Guyatt GH, Wyer PC, et al. Users' guides to the medical
literature: XXII: how to use articles about clinical decision rules.
Evidence-Based Medicine Working Group. JAMA 2000;284:79-84.
2 Johannson KA, Elicker BM, Vittinghoff E, et al. A diagnostic model for
chronic hypersensitivity pneumonitis. Thorax 2016;71:951-4.
3 Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of
hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952-8.
Conflict of Interest:
Yves Lacasse was the principal investigator of the HP Study. All co-authors of this letter were co-investigators of the HP Study.
We thank Cardwell et al for their thoughtful comments on our paper.[1] The two alternative scoring systems did not demonstrate improved discrimination or calibration in our large dataset of AECOPD admissions. The authors suggest employing the Salford-NEWS only in patients ‘at risk’ of hypercapnic respiratory failure however, this introduces a subjective element that may negate the benefits of an objective physiological scoring system. As we emphasised in what we believe was a balanced discussion, patients with COPD should be managed in the right place by specialists and on-going education is crucial to avoid potential harms associated with misinterpretation of the NEWS alluded to by Cardwell and colleagues. Our article adds evidence that suggested RCP thresholds would indeed lead to unnecessary callouts in such patients. However, as we proposed, rather than abandon a scoring system that provides the significant advantages of standardisation and familiarity, it is possible to individualise patient management. For example, lowering observation frequency in a patient who is clinically ‘stable’, not increasing oxygen delivery if the prescribed target saturation is achieved, or taking into account prior/baseline physiology when deciding observation frequency and whether a senior review is required. Indeed a senior review may be appropriate to interpret whether the patient is at risk of hypercapnic respiratory failure and be able to advise on appropriate targets and level of mon...
Show MoreDear Editors,
We are writing to comment on the work entitled “Alveolar macrophage-derived microvesicles mediate acute lung injury” published by Dr. Soni et al on Thorax 2016; 71:1020-1029[1].
Our group focuses on lung extracellular vesicle (EV) research and also studied the inhaled LPS-induced EVs in mouse models. Based on our experience, we raise the following comments to the work done by Dr. Soni et al and wish to draw attentions to future EV researchers. EV research is a novel field and carries a promising potential for the development of diagnostic and therapeutic agents. However, given the early stage of EV research, particular in the field of lung injury, the consistency of results relies largely on the precise techniques used in the isolation and characterization of these vesicles.
Briefly, EV is currently classified into three major categories per the definition of Society of extracellular vesicle research [2]. Apoptotic bodies (ABs) are the largest sizes of EVs usually larger than 1 µm and often resulted from cell death. Microvesicles (MVs) are the middle sized EVs (200 nm-1 µm) and are generated via plasma membrane budding. Exosomes (Exos) are the smallest EVs (less than 200 nm) and often generated from IVB-ER-Golgi system. Due to the different mechanisms of generation, MVs and Exos usually favor different compositions and subsequently may carry differential downstream biological functions[3 4]. For example, Exos have been reported to carry t...
Show MoreI enjoyed reading Hodgson et al’s validation study on Early Warning Scores (EWS) in patients admitted with an exacerbation of COPD. The current problem with EWS such as the National Early Warning Score (NEWS) in such patients is that the score is used in two contexts.
The first is in the initial triage of patients on arrival to hospital based on their early risk of death. NEWS is well validated in this context, and I wholeheartedly agree that NEWS is the best tool for this at present; patients at risk of type 2 respiratory failure, with target oxygen saturations of 88-92%, are at a high risk of death in hospital and identifying these patients early to enable senior review is entirely appropriate.
The problem comes with second use of NEWS – as a “track and trigger” tool used to monitor patients during their inpatient stay, with a rising score indicating deterioration, risk of death and the need for intervention. Hodgson et al have confirmed our finding that NEWS lacks specificity for patients with COPD. These patients will often have persistently high NEWS even when stable, well into their admission, and the actions this is supposed to trigger (hourly observations, senior review, etc.) are no longer appropriate. This leads to alarm fatigue, with high scores being ignored, increasing the risk of a true deterioration not being acted upon.
The proposals of Hodgson et al that such patients should have individually assigned observation frequencie...
Show MoreWe read the paper of Hodgson and colleagues with interest.1 Unfortunately, we note that the Salford-NEWS system (observation chart based on target Oxygen saturation prescription) has been applied in this study to all patients with a diagnosis of acute exacerbation of COPD (AECOPD) whereas we proposed applying this system for all patients at risk of type 2 (hypercapnic) respiratory failure, a group which includes many but not all patients with AECOPD and a number of patients with other conditions.2 Around 86% of those prescribed the lower range of Oxygen saturation (88-92%) in Salford are COPD patients judged to be at risk of hypercapnia, the remainder have conditions such as morbid obesity, neuro-muscular disorders, or complex lung diseases.3 Given this key difference in rationale we suggest that the Salford-NEWS system has been inappropriately applied in this study; hence, the conclusions have to be interpreted with extreme caution.
When comparing NEWS with Salford-NEWS, it is clear that none of the systems had acceptable sensitivity at score thresholds of 5 and 7, and the most consistently reliable result from using either of them is the negative predictive value, which was similar. It was also evident that Salford-NEWS had better specificity at 91% and 95% compared to 57% and 80% for NEWS at score thresholds of 5 and 7 respectively. Since the increased sensitivity in NEWS is achieved at the expense of high “callout” rates, and low positive predictive value (8%...
Show MoreDear Editor, We thank Dr Mansell for her comments regarding our recently published trial. [1] We agree that there are different phenotypic variations within the obesity hypoventilation syndrome (OHS), although it remains to be determined whether OHS with co-existent obstructive sleep apnoea (OSA) responds differently to treatment in comparison to OHS without OSA. [2] Acknowledging that the presence and severity of OSA in...
We read with great interest the article by Howard et al[1] and commend the authors on this excellent piece of work. However, we wish to raise several points for consideration of this work in a clinical context. Firstly, it is not clear whether the patients being treated were truly patients with obesity hypoventilation failure (OHS) or whether in fact they had hypercapnic obstructive sleep apnoea (OSA). There is in...
We thank Professors Lipworth and Anderson for their very thoughtful comments in their response to our piece1, and for pointing out clear strategies for treating obesity-associated asthma without expensive therapies, e.g., with improved delivery of inhaled corticosteroids and/or weight reduction.
It should be noted however, that the focus of the piece was on mechanisms by which obesity might cause asthma,...
We read with interest the state of the art review by Umetsu on mechanisms by which obesity impacts asthma [1]. He has clearly outlined the extent to which molecular targets, both within allergic (T-helper 2 [TH2]) and non-allergic mechanistic pathways of asthma, need further evaluation and drug development for obese asthmatics. This was on the basis that current standard therapies for asthma such as inhaled corticoste...
We thank Dr. Lacasse and the HP Study Group for their correspondence regarding 'A diagnostic model for chronic hypersensitivity pneumonitis', and appreciate their thoughtful consideration of our work.(1) We agree that these two studies are complementary, and hope that both will serve to improve diagnostic accuracy in the evaluation of patients with suspected HP. We further concur that much work remains to be done to advan...
To the Editor,
The diagnosis of hypersensitivity pneumonitis (HP) is difficult and often relies on an array of clinical symptoms and signs developed in an appropriate setting, with the demonstration of radiographic and tomographic abnormalities, serum precipitating antibodies against offending antigens, a lymphocytic alveolitis on bronchoalveolar lavage, and/or a granulomatous reaction on lung biopsies. Taken...
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