I was surprised to see figure 2 in the paper by Stanojevic et al (1) on assessing paediatric FEV1 reproducibility as, on the face of it, the authors may have fallen into a notorious statistical trap. A change in any variable (FEV1, blood pressure etc) is ALWAYS negatively correlated with the initial value because if x is initial value then y-x is the change, so inevitably related. If as an example one uses two separate sets of 100 normally distributed random numbers, each set with mean 100 and standard deviation 12 to mimic percent FEV1 and plot the first set as X against the difference between the two sets (Y-X) it will show an entirely spurious negative correlation (r = -0.7) with typically around 50% of the ‘variance’ explained. Altman(2) instead has recommended plotting a change against their average as an improved way of assessing the true relationship and using identical values, the spurious correlation disappears.
1. Stanojevic S, Filipow N, Ratjen F. Paediatric reproducibility limits for the forced expiratory volume in 1 s. Thorax 2020;75:891-896.
2. Altman DG. From: Practical statistics for medical research. Chapman and Hall, Boca Raton, USA. 1999:282-285.
We thank Dr. Bhakta and colleagues for their interest in our article on the use of extracorporeal CO2 removal (ECCO2R) in patients with stable COPD and chronic hypercapnia (1).
Bhakta et al. pointed out the role of non invasive ventilation (NIV) to treat chronic hypercapnic respiratory failure by improving alveolar ventilation. The Authors additionally argued that, in evaluating the efficacy of ECCO2R in hypercapnic COPD stable patients who have failed NIV therapy, we only concentrated on the hypercapnic rather than the hypoxic aspects, pointing out that in this population symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation.
These points of discussion give us the opportunity to better explain the ECCO2R functioning and consequently the methodology of our study.
ECCO2R refers to an extracorporeal circuit that is able to selectively extract carbon dioxide from blood with little to no effect on oxygenation. Various ECCO2R systems are now available. In addition to PaCO2 baseline level, the ability of different ECCO2R devices to eliminate CO2 is dependent upon two important determinants: 1) the surface area available for gas exchange and 2) the blood flow rate (2). Moreover, the partial pressure gradient of the gas across the membrane can be obtained by using oxygen or air as sweep gas, according to Fick’s law of diffusion. Because in minimally invasive veno-venous ECCO 2 R systems the ratio of catheter...
We thank Dr. Bhakta and colleagues for their interest in our article on the use of extracorporeal CO2 removal (ECCO2R) in patients with stable COPD and chronic hypercapnia (1).
Bhakta et al. pointed out the role of non invasive ventilation (NIV) to treat chronic hypercapnic respiratory failure by improving alveolar ventilation. The Authors additionally argued that, in evaluating the efficacy of ECCO2R in hypercapnic COPD stable patients who have failed NIV therapy, we only concentrated on the hypercapnic rather than the hypoxic aspects, pointing out that in this population symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation.
These points of discussion give us the opportunity to better explain the ECCO2R functioning and consequently the methodology of our study.
ECCO2R refers to an extracorporeal circuit that is able to selectively extract carbon dioxide from blood with little to no effect on oxygenation. Various ECCO2R systems are now available. In addition to PaCO2 baseline level, the ability of different ECCO2R devices to eliminate CO2 is dependent upon two important determinants: 1) the surface area available for gas exchange and 2) the blood flow rate (2). Moreover, the partial pressure gradient of the gas across the membrane can be obtained by using oxygen or air as sweep gas, according to Fick’s law of diffusion. Because in minimally invasive veno-venous ECCO 2 R systems the ratio of catheter blood flow rate to cardiac output is relatively low, the application of oxygen sweep gas is not sufficient to improve oxygenation (3,4).
However, hypercapnic respiratory failure is not necessarily associated with severe hypoxemia, especially in stable hypercapnic COPD patients in whom the presence of hypercapnia has been shown to be a determinant of mortality (5-7).
Actually, the main mechanisms of NIV effectiveness in such population include the impact of the reduced lung hyperinflation on respiratory muscle workload and the increased ventilatory chemo-sensitivity to CO2 (8). In addition, most of the evidences on the use of NIV in patients with stable COPD compared the effects of domiciliary NIV+ long long-term oxygen therapy (LTOT) to LTOT alone (9).
In our study we included 10 severe stable COPD patients with hypercapnia refractory to chronic NIV in terms of arterial blood gases. As mentioned, IPAP was set at 19.3±1.7 and EPAP 4.2±0.02 cmH20. NIV average use was 5.8±1.1hours/night, so the compliance was rather good. Most of patients used LTOT (70%). Obviously, during ECCO2R trial additional oxygen therapy was added if needed and FiO2 was adjusted to maintain SaO2 between 88 and 92%.
The second point concerns how to capitalize the benefits derived from the observed transiently improvement in the arterial blood gas values. In fact, in the cohort of patients able to complete the 24 hours treatment, the effect on CO2 reduction was retained for 48–96 hours after ECCO2R discontinuation (1). We hypothesized that removing CO2 through the extracorporeal circuit may empty parts of the tissue CO2 stores, allowing transient normocapnia during spontaneous breathing. The mechanism of alveolar hypoventilation, as unique factor for the development and maintenance of chronic hypercapnia, is clearly not the only physiological explanation. Moreover, we are often led to translate the physiopathology of COPD exacerbation, for which we are more confident, to the chronic stable condition of the disease. The truth is that the mechanisms underlying this response are not yet identified.
About the third point, we regret that the Authors did not notice the HCO3- baseline values in table 1. In addition, bicarbonates remained stable during the time course of the trial (figure 2). In fact, ECCO2R is not aimed to “normalize” CO2, but just to lower its levels, keeping it reduced for a long period of time.
Finally, we strongly agree that in severe COPD patients, CO2 load is not the sole mediator of improved outcomes. Our manuscript did not touch any patient-related outcomes. However being a proof of concept feasibility study, we focused exclusively to detect a signal whether ECCO2R may provide a time window “free” from hypercapnia in this population. However, the study demonstrated the feasibility of the hypothesis that ECCO2R may improve CO2 clearance in patients with chronic hypercapnia unresponsive to NIV.
To conclude, ECCO2R could have important implications for the care of stable COPD patients and for the design of future investigations aiming to assess how many hours of ECCO2R are needed to provide the longest time window “free” from hypercapnia, detecting the ideal target population ( ECCO2R responders) and clinical benefits such as number of disease-related hospitalisations, improvement of dyspnea, exercise tolerance and health-related quality of life.
References
1. Pisani L, Nava S, Desiderio E, Polverino M, Tonetti T, Ranieri VM. Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: a proof-of-concept study Thorax. 2020;75(10):897-900.
2. Karagiannidis C, Strassmann S, Brodie D, Ritter P, Larsson A, Borchardt R, Windisch W. Impact of membrane lung surface area and blood flow on extracorporeal CO2 removal during severe respiratory acidosis. Intensive Care Med Exp. 2017;5(1):34
3. Schmidt M, Tachon G, Devilliers C, Muller G, Hekimian G, Brechot N, Merceron S, Luyt CE, Trouillet JL, Chastre J, Leprince P, Combes A: Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults. Intensive Care Med 2013, 39: 838-846.
4. Karagiannidis C, Kampe KA, Sipmann FS, Larsson A, Hedenstierna G, Windisch W, Mueller T.Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations. Crit Care. 2014;18(3):R124
5. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT Investigators (Study to understand prognoses and preferences for outcomes and risks of treatments). Am J Respir Crit Care Med 1996; 154: 959–967.
6. Costello R, Deegan P, Fitzpatrick M, et al. Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis. Am J Med 1997; 102: 239–244.
7. Foucher P, Baudouin N, Merati M, et al. Relative survival analysis of 252 patients with COPD receiving long-term oxygen therapy. Chest 1998; 113: 1580–1587
8. Turkington PM, Elliott MW. Rationale for the use of non-invasive ventilation in chronic ventilatory failure. Thorax 2000; 55: 417–423.
9. Begum E, Oczkowski S, Rochwerg B et al. European Respiratory Society guidelines on long-term home non-invasive ventilation for management of COPD. European Respiratory Journal 2019 54: 1901003
Title: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
Pradipta Bhakta, Antonio M. Esquinas, Brian O’Brien.
Authors:
1. Dr. Pradipta Bhakta (MD, MNAMS, FCAI, EDRA, EDIC)
Consultant,
Department of Anaesthesia and Intensive Care,
University Hospital Kerry, Tralee, Kerry, Ireland.
Phone: 00353894137596.
Email: bhaktadr@hotmail.com
2. Dr. Antonio M. Esquinas (PhD, MD)
Consultant,
Department of Intensive Care,
Hospital Morales Meseguer,
Murcia, Spain.
Phone: 0034609321966
Email: antmesquinas@gmail.com
3. Dr. Brian O’Brien [FCARCSI, FJFICMI, FCICM (ANZ)]
Consultant and Chair,
Department of Anaesthesia and Intensive Care,
Cork University Hospital, Cork, Ireland.
Mobile: 00353877931656
Email: drbobrien@hotmail.com
Authors and their role:
1. Dr. Pradipta Bhakta: Was involved analysis of the article, writing and editing the letter.
2. Dr. Antonio M. Esquinas: Was involved analysis of the article, writing and editing the letter.
3. Dr. Brian O’Brien: Was involved analysis of the article, writing and editing the letter.
Corresponding Author: Dr. Pradipta Bhakta,
Consultant,
Departm...
Title: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
Pradipta Bhakta, Antonio M. Esquinas, Brian O’Brien.
Authors:
1. Dr. Pradipta Bhakta (MD, MNAMS, FCAI, EDRA, EDIC)
Consultant,
Department of Anaesthesia and Intensive Care,
University Hospital Kerry, Tralee, Kerry, Ireland.
Phone: 00353894137596.
Email: bhaktadr@hotmail.com
2. Dr. Antonio M. Esquinas (PhD, MD)
Consultant,
Department of Intensive Care,
Hospital Morales Meseguer,
Murcia, Spain.
Phone: 0034609321966
Email: antmesquinas@gmail.com
3. Dr. Brian O’Brien [FCARCSI, FJFICMI, FCICM (ANZ)]
Consultant and Chair,
Department of Anaesthesia and Intensive Care,
Cork University Hospital, Cork, Ireland.
Mobile: 00353877931656
Email: drbobrien@hotmail.com
Authors and their role:
1. Dr. Pradipta Bhakta: Was involved analysis of the article, writing and editing the letter.
2. Dr. Antonio M. Esquinas: Was involved analysis of the article, writing and editing the letter.
3. Dr. Brian O’Brien: Was involved analysis of the article, writing and editing the letter.
Corresponding Author: Dr. Pradipta Bhakta,
Consultant,
Department of Anaesthesia and Intensive Care,
University Hospital Kerry, Tralee, Kerry, Ireland.
Phone: 00353894137596
Email: bhaktadr@hotmail.com
Category of the article: Correspondence in response to article by Pisani L et al.
Running Title: Letter replying to Pisani L et al.
Financial support: No funding other than personal was used in conducting the audit as well as writing the manuscript. We declare that we have no financial and/or personal relationships with other people or organizations that could inappropriately influence (bias) our work.
Conflict of Interest: The authors report no conflicts of interest.
Ethical Approval: Not applicable.
Word Count: 500.
Figure no: 0.
Table No: 0.
To The Editor,
We read with interest the proof-of-concept by Pisani and colleagues and congratulate them on this important work.1 We believe that several methodological details warrant analysis to facilitate extrapolation of their findings into the clinical context.
In particular, it appears the authors characterise non-invasive ventilation (NIV) entirely as a mode of carbon dioxide (CO2) removal. We would emphasize its value as a modality to improve oxygenation. Many patients with chronic obstructive pulmonary disease (COPD) are hypoxic in part because of alveolar displacement of oxygen by expired CO2.2 The consequent type 2 respiratory failure, characteristic of advanced COPD with alveolar hypoventilation, by definition incorporates accompanying hypoxia.3 In evaluating the efficacy of ECCO2R in such patients, they only concentrated on the hypercapnic rather than the hypoxic aspect. NIV however offers both benefits.4 In selecting hypercapnic patients who have failed NIV therapy for the ECCO2R group, we would suggest that in such severe cases symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation. Effectively oxygen (O2) replaces CO2 eliminated from the alveoli, haemoglobin and cells. But if this aspect is ignored, the use of ECCO2R for 24 hours cannot contribute in the longer term. If we have understood correctly, in the ECCO2R rather than use additional O2, air flow was used to eliminate CO2. Patients in the ECCO2R group, having failed NIV trials in the preceding 6 months, were spontaneously breathing room air. This raises the question of how they were able to tolerate this. In this context we also wonder if the cases were matched for disease severity. Is it possible that milder cases were included, perhaps who were intolerant of NIV due to claustrophobia, discomfort or asynchrony? These points might be clarified further.
A second broad point we would raise is the acceptance of normalized pH in chronic COPD patients with chronic acid-base disturbances, which are typically compensated by the kidney and by buffers in the circulation.5 We agree that in patients with severely diseased functional lung tissue the elimination of CO2 can provide temporary improvement in the arterial blood gas values, but wonder how the authors might speculate on future innovations to extend or capitalise on these benefits.
Thirdly, while studying severe cases of COPD, the study included patients with pH levels above 7.35 while their PaCO2 exceeded 50 mmHg. There is no value given for HCO3 which is clearly important. Ideally full data might be provided to allow categorisation as per the GOLD staging classification.6
Fourthly, in highlighting the role of ECCO2R in severe COPD patients, they have emphasised the failure of NIV. It ought to be observed that ECCO2R has similarly failed to benefit patients with acute respiratory distress syndrome.7 In severe cases of COPD, CO2 load is not the sole mediator of improved outcomes nor of symptomatic benefit, although it is a major issue with multiple adverse effects.3 We would welcome the authors’ views on these points and their thoughts on how their findings may become relevant to clinical practice in the future.
Pradipta Bhakta,
Antonio M. Esquinas,
Brian O’Brien.
References
1. Pisani L, Nava S, Desiderio E, Polverino M, Tonetti T, Ranieri VM. Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: a proof-of-concept study [published online ahead of print, 2020 Aug 5]. Thorax. 2020;thoraxjnl-2020-214744. doi:10.1136/thoraxjnl-2020-214744.
2. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199-208.
3. Agustí A, Hogg JC. Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease. N Engl J Med. 2019;381(13):1248-1256.
4. Coleman JM 3rd, Wolfe LF, Kalhan R. Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc. 2019;16(9):1091-1098.
5. Bruno CM, Valenti M. Acid-base disorders in patients with chronic obstructive pulmonary disease: a pathophysiological review. J Biomed Biotechnol. 2012;2012:915150.
6. Singh D, Agusti A, Anzueto A, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019;53(5):1900164.
7. Fitzgerald M, Millar J, Blackwood B, et al. Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. Crit Care. 2014;18(3):222.
Dear Editors,
This journal published the BTS guidelines for the management of pulmonary nodules in August 2015 (1), leading to widespread evidence-based management of this common clinical problem. The use of the Herder score (2) to estimate or predict the likelihood of malignancy has since become routine in lung cancer MDMs around the country.
We therefore wish to highlight that the Herder prediction model was developed using the intensity of FDG uptake (absent, faint, moderate or intense) from the uncorrected PET images. However, as far as we are aware, lung cancer MDMs routinely assess the intensity of FDG uptake from the corrected images which is not in accordance with the original Herder model.
The use of uncorrected images in the original Herder study (2) to distinguish between uptake categories potentially alters the perceived evidence base of the recommendations in the BTS guidelines (1) to distinguish between faint and moderate uptake according to mediastinal blood pool given that this scale of uptake was not used in the original score, has not been validated and could mean we are not using the correct category in the risk model.
Furthermore, when considering the widespread use of the Herder score, it should be appreciated that it was formulated from patients scanned between 1997 and 2001. The Herder paper describes that “emission scans were acquired in a two-dimensional mode … and were reconstructed using ordered subset expectation maximisa...
Dear Editors,
This journal published the BTS guidelines for the management of pulmonary nodules in August 2015 (1), leading to widespread evidence-based management of this common clinical problem. The use of the Herder score (2) to estimate or predict the likelihood of malignancy has since become routine in lung cancer MDMs around the country.
We therefore wish to highlight that the Herder prediction model was developed using the intensity of FDG uptake (absent, faint, moderate or intense) from the uncorrected PET images. However, as far as we are aware, lung cancer MDMs routinely assess the intensity of FDG uptake from the corrected images which is not in accordance with the original Herder model.
The use of uncorrected images in the original Herder study (2) to distinguish between uptake categories potentially alters the perceived evidence base of the recommendations in the BTS guidelines (1) to distinguish between faint and moderate uptake according to mediastinal blood pool given that this scale of uptake was not used in the original score, has not been validated and could mean we are not using the correct category in the risk model.
Furthermore, when considering the widespread use of the Herder score, it should be appreciated that it was formulated from patients scanned between 1997 and 2001. The Herder paper describes that “emission scans were acquired in a two-dimensional mode … and were reconstructed using ordered subset expectation maximisation with two iterations and 16 subsets followed by post smoothing… using a Hanning 0.5 filter”.
PET cameras and reconstruction techniques have advanced considerably since then and the imaged intensity of FDG uptake within nodules <3cm in diameter acquired on modern cameras is likely to be quite different to twenty years ago. In particular it is now standard to have 3-dimensional mode acquisition and reconstructions which routinely include point spread function and time-of-flight data. This results in an increase in the SUVmax of small nodules and a potential upgrade in the avidity category of these lesions.
A validation study by Al-Ameri et al published in 2015 (3) provides some reassurance the use of corrected images on modern scanners is still sufficiently accurate as they used corrected images to distinguish between faint, moderate and intense FDG uptake by the use of SUVmax ≤2.5, 2.6-10 and >10 as parameters respectively.
There is now widespread use of PET-CT to characterise pulmonary nodules and increasing use of electronic databases to record patient characteristics and outcomes. We suggest that this data could be used to produce an updated version of the Herder model. For simplicity, and given its previous proven accuracy in the validating study, the same variables (age, smoking, previous history of cancer, diameter, spiculation, upper lobe) as in the original Herder model could be used. Large sample sizes and potential multi-centre data aggregation would result in model more accurate and appropriate to modern cameras than the original Herder score.
We therefore suggest that the recommendation to use the Herder model to characterise pulmonary nodules is reviewed addressing:
1. Clarifying whether the corrected or uncorrected PET images should be used.
2. Determining whether the scale for distinguishing between faint and moderate uptake using mediastinal blood pool is sufficiently evidence-based.
3. Supporting the development of an updated model using data acquired on modern day PET-CT scanner technology.
References:
1. Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015;70 Suppl 2:ii1-ii54.
2. Herder GJ, van Tinteren H, Golding RP, Kostense PJ, Comans EF, Smit EF, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest. 2005;128(4):2490-6.
3. Al-Ameri A, Malhotra P, Thygesen H, Plant PK, Vaidyanathan S, Karthik S, et al. Risk of malignancy in pulmonary nodules: A validation study of four prediction models. Lung Cancer. 2015;89(1):27-30.
We have read with interest the article by Taylor et al. concerning "the mechanism of lung development in the etiology of congenital malformations of the pulmonary airways in adults". The authors discussed the etiology of congenital malformations of the pulmonary airways, suggesting a partial modification of lung development with a potential risk of malignancy.
Although we generally agree with their assessment, there are some weaknesses in their work that we would like to highlight as well as some points on which we would like to propose an alternative point of view. Different transcription factors known to be involved in lung development have already been studied in CPAM. Two of them, SOX2 and SOX9 are described as important in the spatiotemporal branching development since the pseudoglandular stage [1, 2]. In CPAM, SOX2 is present in both CPAM types (1 and 2), but their expression differs between them [3]. In addition, previously published papers have shown persistent SOX2 expression in healthy lung, which is not the case in this paper. Unfortunately, Talyor et al present "adult" samples and not adjacent healthy. However, this is not sufficient to explain these differences and classical tissues from children should have been included to demonstrate this point. Moreover, a difference in the cells forming the two types of CPAM has already been described by immunohistochemistry and proteomic results. Nevertheless these points are not addressed in t...
We have read with interest the article by Taylor et al. concerning "the mechanism of lung development in the etiology of congenital malformations of the pulmonary airways in adults". The authors discussed the etiology of congenital malformations of the pulmonary airways, suggesting a partial modification of lung development with a potential risk of malignancy.
Although we generally agree with their assessment, there are some weaknesses in their work that we would like to highlight as well as some points on which we would like to propose an alternative point of view. Different transcription factors known to be involved in lung development have already been studied in CPAM. Two of them, SOX2 and SOX9 are described as important in the spatiotemporal branching development since the pseudoglandular stage [1, 2]. In CPAM, SOX2 is present in both CPAM types (1 and 2), but their expression differs between them [3]. In addition, previously published papers have shown persistent SOX2 expression in healthy lung, which is not the case in this paper. Unfortunately, Talyor et al present "adult" samples and not adjacent healthy. However, this is not sufficient to explain these differences and classical tissues from children should have been included to demonstrate this point. Moreover, a difference in the cells forming the two types of CPAM has already been described by immunohistochemistry and proteomic results. Nevertheless these points are not addressed in these articles and no distinction has been made between the two CPAM subtypes. Without any quantification of the immunological staining experiments, the presented results are weak and are not correlated with the previous published articles.
The potential risk of malignancy remains an important point of discussion in every publication because of the impact of clinical management for the patient [4-6]. Recently Lezmi et al. presented transcriptomic results of laser microdissected cystic epithelium having deregulated genes, known to be involved in cancer and the development process [7]. Swarr et al. demonstrated by gene set enrichment analysis (GSEA) an increased level of the PI3K-AKT-mTOR and Myc signaling pathways among down-regulated transcripts [2]. The same results were highlighted in proteomic experiments [3]. These modifications may have an impact on the type of CPAM formation, but also play a role in cell metaplasia. The description of the decrease in RALDH-1 staining is interesting, with a possible impact on tumoral transformation. However, a simple immunostaining without quantification seems insufficient to support this hypothesis. Altogether these results are exciting, but a deeper analysis with more recent citations would have given higher impact to their article.
1. Danopoulos S, Alonso I, Thornton ME, Grubbs BH, Bellusci S, Warburton D, Al Alam D: Human lung branching morphogenesis is orchestrated by the spatiotemporal distribution of ACTA2, SOX2, and SOX9. Am J Physiol Lung Cell Mol Physiol 2018, 314:L144-L149.
2. Swarr DT, Peranteau WH, Pogoriler J, Frank DB, Adzick NS, Hedrick HL, Morley M, Zhou S, Morrisey EE: Novel Molecular and Phenotypic Insights into Congenital Lung Malformations. Am J Respir Crit Care Med 2018.
3. Barazzone-Argiroffo C, Lascano Maillard J, Vidal I, Bochaton-Piallat ML, Blaskovic S, Donati Y, Wildhaber BE, Rougemont AL, Delacourt C, Ruchonnet-Metrailler I: New insights on congenital pulmonary airways malformations revealed by proteomic analyses. Orphanet J Rare Dis 2019, 14:272.
4. Casagrande A, Pederiva F: Association between Congenital Lung Malformations and Lung Tumors in Children and Adults: A Systematic Review. J Thorac Oncol 2016, 11:1837-1845.
5. Pogoriler J, Swarr D, Kreiger P, Adzick NS, Peranteau W: Congenital Cystic Lung Lesions: Redefining the Natural Distribution of Subtypes and Assessing the Risk of Malignancy. Am J Surg Pathol 2017.
6. Stanton M: The argument for a non-operative approach to asymptomatic lung lesions. Semin Pediatr Surg 2015, 24:183-186.
7. Lezmi G, Vibhushan S, Bevilaqua C, Crapart N, Cagnard N, Khen-Dunlop N, Boyle-Freyssaut C, Hadchouel A, Delacourt C: Congenital cystic adenomatoid malformations of the lung: an epithelial transcriptomic approach. Respir Res 2020, 21:43.
The sneeze is depicted as horizontal, presumably for the camera. In a real sneeze, the head first tends to first tilt back, but during the actual sneeze, tends to point downwards. This means that large droplets tend to move toward the floor. Would have been nice to see a P2/N95 mask. Apart from that, a useful paper.
Dear Editor,
We agree with Koeckerling et al. that awake prone positioning, if proven beneficial, could provide a simple resource-conserving intervention that improves outcomes in COVID-19, especially in the resource-limited countries where even with mitigation strategies critical care bed demand is modelled to outstrip supply by a factor of 25.1,2
Currently, our knowledge about prone positioning is extrapolated from studies in non-awake, mechanically ventilated patients and so these proposed benefits remain theoretical.3-6
In addition to the various small-scale observational studies mentioned by Koeckerling et al., a recently published observational study of 24 awake COVID-19 patients concluded that awake prone positioning was well tolerated. However, the numbers were too small to confirm or refute any benefit in this population.7 Randomised control trial (RCT) is the gold standard for evidence in awake prone positioning in COVID-19 population. However, RCT will be a very difficult approach for this intervention due to the likelihood of a lack of equipoise amongst clinicians to recruit. Following national guidelines, many departments would implement this intervention as the standard of care. Awake prone positioning also appears to be a safe intervention in awake patients and may slow the respiratory deterioration in selected patients with COVID-19.1
Following the recent Intensive Care Society (ICS) guideline, clinicians within our institution ha...
Dear Editor,
We agree with Koeckerling et al. that awake prone positioning, if proven beneficial, could provide a simple resource-conserving intervention that improves outcomes in COVID-19, especially in the resource-limited countries where even with mitigation strategies critical care bed demand is modelled to outstrip supply by a factor of 25.1,2
Currently, our knowledge about prone positioning is extrapolated from studies in non-awake, mechanically ventilated patients and so these proposed benefits remain theoretical.3-6
In addition to the various small-scale observational studies mentioned by Koeckerling et al., a recently published observational study of 24 awake COVID-19 patients concluded that awake prone positioning was well tolerated. However, the numbers were too small to confirm or refute any benefit in this population.7 Randomised control trial (RCT) is the gold standard for evidence in awake prone positioning in COVID-19 population. However, RCT will be a very difficult approach for this intervention due to the likelihood of a lack of equipoise amongst clinicians to recruit. Following national guidelines, many departments would implement this intervention as the standard of care. Awake prone positioning also appears to be a safe intervention in awake patients and may slow the respiratory deterioration in selected patients with COVID-19.1
Following the recent Intensive Care Society (ICS) guideline, clinicians within our institution have implemented awake prone positioning as a standard of care in suspected or confirmed COVID-19 patients which we expect is not unique. 8
These provide an opportunity to investigate the possible benefit of awake prone positioning using anonymised routinely collected healthcare data to compare outcomes in supine and prone cohorts before and after the implementation of awake prone positioning. We have developed a robust protocol that have been approved by the Health Research Authority for analysis of this data, but our sample is too small. We call for collaboration between sites that have implemented similar guidance to generate robust outcomes from data already in existence but siloed between sites.
Patients included in the study are all awake, inpatients aged >18years with PCR confirmed nasal swabs for COVID-19 and hypoxic respiratory failure requiring hospitalisation.
We propose collecting data on outcome measures, including all-cause mortality, oxygen consumption, the requirement for invasive mechanical ventilation, length of non-invasive ventilation and length of stay. Propensity score matching will be undertaken to allow comparison between supine and prone cohorts based on common participant descriptors such as age, sex, and gender. However, emerging concerns for COVID study design, such as collider bias 9 (where a factor, such as smoking history, associates both with having a COVID-19 test and disease prognosis), present serious challenges for robust research conclusions; thus, while further patient characteristics will be collected (ethnicity, symptom onset, Rockwood frailty score, drug history, blood results including arterial blood gases), final matching factors will be determined as data from the Office of National Statistics allow for a better understanding of potential colliders to avoid inducing a false association.
Differences in O2 consumption and length of stay in hospital by awake prone positioning status will be estimated using multiple linear regression adjusting for propensity score matching (PSM). Power analyses suggest that with a total sample size of 600 patients (300 supine and 300 prone) we have 80% power to estimate a difference in O2 consumption of at least 20%, a plausible effect size given prior literature.
Risk of all-cause mortality will be estimated using multiple logistic regression adjusting for PSM. With 600 patients, as described above, we will have 80% power to estimate an odds ratio of at least 1.6 or a 60% difference in risk of dying from any cause.
Now is the time to collect pragmatic, reliable evidence about the safety and efficacy of awake prone positioning in COVID-19, so that we may overcome the COVID-19 pandemic in resource-limited settings and will be better prepared for future pandemic peaks.
If you think you can help, please contact raha.west@nhs.net where we will take you through the process and acknowledge your involvement on this worthwhile endeavour.
References
1. Koeckerling D, Barker J, Mudalige NL, et al Awake prone positioning in COVID-19 Thorax Published Online First: 16 June 2020. doi: 10.1136/thoraxjnl-2020-215133
2. https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-...
3. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. New England Journal of Medicine. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103
4. Munshi L, del Sorbo L, Adhikari NKJ, et al. Prone position for acute respiratory distress syndrome: A systematic review and meta-analysis. Annals of the American Thoracic Society. 2017;14(February):S280-S288. doi:10.1513/AnnalsATS.201704-343OT
5. Bloomfield R, Noble DW, Sudlow A. Prone position for acute respiratory failure in adults. Cochrane Database of Systematic Reviews. 2015;2015(11):CD008095. doi:10.1002/14651858.CD008095.pub2
6. Sud S, Friedrich JO, Adhikari NKJ, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: A systematic review and meta-analysis. CMAJ. 2014;186(10):E381-90. doi:10.1503/cmaj.140081
7. Elharrar X, Trigui Y, Dols A, et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA. Published online May 15, 2020. doi:10.1001/jama.2020.8255
8. Bamford P, Bentley A, Dean J, Whitmore D, Wilson -Baig N. ICS Guidance for Prone Positioning of the Conscious COVID Patient 2020
9. Theoretical Motivation for Considering Collider Bias. Using AscRtain. (2020). Retrieved 17 June 2020, from http://apps.mrcieu.ac.uk/ascrtain/
Dear Editor,
I read with interest Editorial by Wang et al. (1) regarding treatment of asthma in Covid-19 pandemic. It has been reported that allergic diseases, asthma, and chronic obstructive pulmonary disease were not risk factors for SARS-CoV-2 infection as shown in an earlier report from China (2). On the other hand, early data from Centre for Disease Control and Prevention (CDC) in the US suggest a higher rate of asthma in patients hospitalized for severe Covid-19 illness (3). On this background, patients with severe and uncontrolled asthma have also been included to be at increased risk of developing more severe Covid-19 according to CDC (3). It is however unclear whether increased risk is also relevant to the paediatric age group.
I agree with the authors that asthma control on a population scale may have improved due to reduced pollution, the use of face masks, better medication adherence and reduced smoking. However, these factors are of lesser importance in the paediatric age group. There is variability in the use of facial masks in different countries. It is most probably that lesser severe illness of Covid-19 in children due to the disease (asthma and respiratory allergy) itself that is offering some kind of protection. That protection seems to more than that being offered by adherence to medical treatment alone. Results from a recent cohort study indicate that children with asthma and allergies have reduced angiotensin-converting enzyme-2 (ACE2) gen...
Dear Editor,
I read with interest Editorial by Wang et al. (1) regarding treatment of asthma in Covid-19 pandemic. It has been reported that allergic diseases, asthma, and chronic obstructive pulmonary disease were not risk factors for SARS-CoV-2 infection as shown in an earlier report from China (2). On the other hand, early data from Centre for Disease Control and Prevention (CDC) in the US suggest a higher rate of asthma in patients hospitalized for severe Covid-19 illness (3). On this background, patients with severe and uncontrolled asthma have also been included to be at increased risk of developing more severe Covid-19 according to CDC (3). It is however unclear whether increased risk is also relevant to the paediatric age group.
I agree with the authors that asthma control on a population scale may have improved due to reduced pollution, the use of face masks, better medication adherence and reduced smoking. However, these factors are of lesser importance in the paediatric age group. There is variability in the use of facial masks in different countries. It is most probably that lesser severe illness of Covid-19 in children due to the disease (asthma and respiratory allergy) itself that is offering some kind of protection. That protection seems to more than that being offered by adherence to medical treatment alone. Results from a recent cohort study indicate that children with asthma and allergies have reduced angiotensin-converting enzyme-2 (ACE2) gene expression due to down-regulation of the ACE2 receptor (4). In this study, ACE2 expression in respiratory cells was lowest in those with both high levels of allergic sensitization and asthma (4). This might explain why children with asthma and allergic sensitization have apparently less serious illness. At present, reduced ACE2 expression appears to be a potential "protective" mechanism of reduced covid-19 severity in children with asthma and respiratory allergy. Furthermore, in the paediatric age group, cross-immunity from exposure to seasonal coronaviruses is also hypothesized as plausible mechanism for relative mild illness in children (5).
CHANDRA SEKHAR DEVULAPALLI chandev@gmail.com
Chandra Sekhar Devulapalli is M.D., Ph.D., Senior Medical Consultant and Paediatrician, Norwegian Labour and Welfare Administration (NAV), Work and Benefits Kristiania, Oslo, Norway.
References
1) Wang R, Bikov A, Fowler SJ. Treating asthma in the COVID-19 pandemicThorax Published Online First: 10 June 2020. doi: 10.1136/thoraxjnl-2020-215118
2) Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China [published online ahead of print, 2020 Feb 19]. Allergy. 2020;10.1111/all.14238. doi:10.1111/all.14238
3) Centers for Disease Control and Prevention. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR. 2020;69.
4) Jackson DJ, Buses WW, Bacharier LB et al. Association of Respiratory Allergy, Asthma and Expression of the SARS-CoV-2 Receptor, ACE2. Journal of Allergy and Clinical Immunology (2020). https://doi.org/10.1016/j.jaci.2020.04.009
5) Devulapalli CS. COVID‐19 is milder in children possibly due to cross immunity. Acta Paediatr. 2020 Jun 10:10.1111/apa.15407. doi: 10.1111/apa.15407. Online ahead of print.
We read with interest the article by Koeckerling et al. (1) regarding ‘Awake Prone
Positioning in COVID’. The authors have discussed the pros and cons of an
intervention that is being widely used during the COVID-19 pandemic. Although
we broadly agree with their assessment, there are some inaccuracies we would
like to point out as well as a few issues where we would like to offer an
alternative viewpoint:
1. Koeckerling and colleagues (1) quote that 78% of patients with severe
ARDS from a study by Ding et al (2) needed intubation. The original study
was performed prior to COVID-19 pandemic and reported that 55% of
patients with moderate to severe ARDS undergoing awake prone
positioning in conjunction with high flow nasal oxygen (HFNO) /non-
invasive ventilation (NIV) avoided intubation. All clinicians would agree that
invasive mechanical ventilation should not be delayed in the face of a
failing non-invasive intervention. The monitoring of the response to any
treatment is key to determining the appropriate management plan.
2. Koeckerling and colleagues report that CT scanning is essential to identify
which patients would benefit from awake prone positioning but this may not
be possible in view of the large numbers of patients. Gattinoni et al. do
describe different phenotypes based on CT appearances, but this is to
explain the pathophysiology of in different ph...
We read with interest the article by Koeckerling et al. (1) regarding ‘Awake Prone
Positioning in COVID’. The authors have discussed the pros and cons of an
intervention that is being widely used during the COVID-19 pandemic. Although
we broadly agree with their assessment, there are some inaccuracies we would
like to point out as well as a few issues where we would like to offer an
alternative viewpoint:
1. Koeckerling and colleagues (1) quote that 78% of patients with severe
ARDS from a study by Ding et al (2) needed intubation. The original study
was performed prior to COVID-19 pandemic and reported that 55% of
patients with moderate to severe ARDS undergoing awake prone
positioning in conjunction with high flow nasal oxygen (HFNO) /non-
invasive ventilation (NIV) avoided intubation. All clinicians would agree that
invasive mechanical ventilation should not be delayed in the face of a
failing non-invasive intervention. The monitoring of the response to any
treatment is key to determining the appropriate management plan.
2. Koeckerling and colleagues report that CT scanning is essential to identify
which patients would benefit from awake prone positioning but this may not
be possible in view of the large numbers of patients. Gattinoni et al. do
describe different phenotypes based on CT appearances, but this is to
explain the pathophysiology of in different phases of acute respiratory
failure due to COVID-19 pneumonia. They and other authors of studies
describing awake prone positioning do not mention CT chest as a pre-
requisite for awake prone positioning. This strategy is based solely on
oxygen requirement. Prone positioning was initiated once patients needed
more than 4 liters/minute or 28% to 40% oxygen and did not meet any
exclusion criteria.
3. Koeckerling and colleagues further suggest that it would be difficult to
maintain awake prone positioning for 12-16 hours, a duration seen to be
essential for survival benefit during mechanical ventilation. Although it is
difficult to tolerate awake prone positioning for long periods, studies have
reported that patients perform several sessions of prone positioning each
day, totaling up to 6 to 12 hours as needed. Patients on mechanical
ventilation tend to have much more advanced ARDS, which may require a
longer duration of prone positioning to get optimal benefit. Patients
undergoing awake prone positioning have earlier and less severe lung
injury and could benefit from a somewhat shorter duration of prone
positioning. This is supported by findings of Coppo et al. (3) demonstrating
better outcome with earlier initiation of prone positioning.
4. Koeckerling and colleagues report that awake prone positioning could
induce cough leading to aerosol generation of virus. Although this is
theoretically possible, there have been no studies that have reported this.
Moreover, when we used this strategy in our own practice, we did not
observe an increased coughing associated with awake prone positioning.
An alternative to awake prone positioning would be use of continuous
positive airway pressure (CPAP) or HFNO which are considered aerosol
generating procedures themselves and we would expect standard
infection, prevention and control measures to be put in place.
5. Koeckerling and colleagues comment that the Intensive Care Society (ICS)
recommends a blanket policy for use of prone positioning. The ICS has
provided a guidance on indications and settings for awake prone
positioning. The guidance does not say that any patients fulfilling the
suitability criteria must undergo awake prone positioning. A number of
societies including the British Thoracic Society, Irish, Italian and German
guidelines recommend the use of CPAP for hypoxaemic respiratory failure
due to COVID-19 with regular monitoring to assess for treatment failure.
Awake prone positioning has been reported to avoid intubation in more
than 50% patients whereas CPAP is associated with a lower success rate
in avoiding invasive mechanical ventilation in COVID pneumonia. (4)
6. As of 5th July 2020 there have been 11,579,892 confirmed cases of
CVOID-19 in 214 countries worldwide with 537173 deaths. This pandemic
has placed a severe strain on ICUs with demand outstripping capacity in
Europe and USA. India is now placed third with 699,402 cases and a rising
death toll. Despite a population of 1·3 billion, India has only 1·9 million
hospital beds, 100,000 Intensive Care Unit (ICU) beds with only 50,000
ventilators that are concentrated in seven (out of 37) states, mostly in the
private sector. (5) Many of the countries which will be most severely
affected by COVID-19 and whose healthcare systems will be overwhelmed
will be in the developing world. We agree with Koeckerling et al. that there
is therefore a powerful argument for the adoption of a simple, inexpensive
strategy in situations of resource limitation.
7. Most data on awake prone positioning is observational and retrospective
with the usual problems inherent in such data. These data therefore need
to be interpreted with caution and a randomised controlled study will be
need to determine the role of awake prone positioning in acute lung injury
in both patients for escalation in a critical care setting and those who are
deemed not for escalation outside the ICU setting (6). A simple
intervention that does not require a CT scan, that can be delivered outside
critical care and could be used in elderly patients who have limits to the
care on offer who are able to lie prone independently could an attractive
intervention in a number of healthcare systems.
References
1. Awake prone positioning in COVID-19. Koeckerling D, Barker J , Mudalige NL, et
al. Thorax 2020. https://thorax.bmj.com/content/thoraxjnl/early/2020/06/15/thoraxjnl-
2020-215133.full.pdf
2. Ding L, Wang L, Ma W, et al. Efficacy and safety of early prone positioning
combined with HFNC or NIV in moderate to severe ARDS: a multi-center
prospective cohort study. Crit Care 2020;24:28.
3.Feasibility and physiological effects of prone positioning in on-intubated
patients with acute respiratory failure due to COVID-19 (PRON-COVID). Coppo
A, Bellani G, Winterton D, et al. Lancet Respir Med 2020
DOI:https://doi.org/10.1016/S2213-2600(20)30268-X
4.COVID-19 in India: State-Wise Estimates of Current Hospital Beds, ICU Beds,
and Ventilators [Internet]. Center for Disease Dynamics, Economics & Policy
5.Severity of respiratory failure and outcome of patients needing a ventilatory
support in the Emergency Department during Italian novel coronavirus SARS-
CoV2 outbreak: Preliminary data on the role of Helmet CPAP and Non-Invasive
Positive Pressure Ventilation. Duca A, Memaj I, Zanardi F et
al. https://doi.org/10.1016/j.eclinm.2020.100419
6.Features of 20133 UK patients in hospital with covid-19 using the ISARIC WHO
Clinical Characterisation Protocol: prospective observational cohort study.
Docherty AB, Harrison EM, GreenCA, et al.
2020;369:m1985 http://dx.doi.org/10.1136/ bmj.m1985
Caretto et al’s brief communication[1] shines some additional light on an unresolved question of the role of alpha-1 antitrypsin deficiency (AATD) screening in patients with bronchiectasis. The authors conclude that testing of an unselected UK population (presumably with a primary diagnosis of bronchiectasis) identifies severe AATD in less than 1% of cases and that routine screening does not significantly impact on clinical management. Whilst these conclusions may be broadly applicable, it may be advisable to qualify the recommendation with some further detail to avoid potential misinterpretation and the consequent complete avoidance of AATD testing in patients with bronchiectasis.
The study rationale originates from apparent conflicting recommendations of guidelines for bronchiectasis[2] and those for AATD[3]. It is stated by the authors that the latter advises AATD testing in all cases of bronchiectasis, whereas the guidelines (in recommendation 1c) in fact advocate testing in cases of ‘unexplained’ bronchiectasis. The use of the term ‘unexplained’ implies the use of a staged approach to the investigation of bronchiectasis with AATD testing reserved for a selected bronchiectasis population in which a diagnosis remains elusive despite clinically appropriate initial investigations.
Studies of bronchiectasis in AATD are few in number and relatively small in size. Nevertheless, there is some consistency in the findings. In their conclusions from a study of t...
Caretto et al’s brief communication[1] shines some additional light on an unresolved question of the role of alpha-1 antitrypsin deficiency (AATD) screening in patients with bronchiectasis. The authors conclude that testing of an unselected UK population (presumably with a primary diagnosis of bronchiectasis) identifies severe AATD in less than 1% of cases and that routine screening does not significantly impact on clinical management. Whilst these conclusions may be broadly applicable, it may be advisable to qualify the recommendation with some further detail to avoid potential misinterpretation and the consequent complete avoidance of AATD testing in patients with bronchiectasis.
The study rationale originates from apparent conflicting recommendations of guidelines for bronchiectasis[2] and those for AATD[3]. It is stated by the authors that the latter advises AATD testing in all cases of bronchiectasis, whereas the guidelines (in recommendation 1c) in fact advocate testing in cases of ‘unexplained’ bronchiectasis. The use of the term ‘unexplained’ implies the use of a staged approach to the investigation of bronchiectasis with AATD testing reserved for a selected bronchiectasis population in which a diagnosis remains elusive despite clinically appropriate initial investigations.
Studies of bronchiectasis in AATD are few in number and relatively small in size. Nevertheless, there is some consistency in the findings. In their conclusions from a study of the distribution of AATD alleles in an unselected bronchiectasis population, the presence of bronchiectasis in PiZ patients was considered by Cuvelier et al[4] to be a consequence of emphysema rather than a primary effect. This association had been previously suggested by small case series[5,6] and, in our subsequent study of 74 individuals with the PiZ phenotype, we were able to demonstrate using quantitative CT imaging that there is a clear association between the severity of emphysema and the severity of bronchiectasis, and a tendency for co-location of the two pathologies[7] (comparable associations between emphysema and bronchiectasis are also seen in patients with non-deficient or usual COPD). Whilst this relationship held true for the majority of our study population, we identified a sub-group of 6 patients in whom the bronchiectasis was of the greatest severity but with a relative paucity of emphysema. This sub-group also included the only 3 patients with cystic bronchiectasis. Our interpretation of these findings was that the sub-group was representative of a distinct clinical phenotype, possibly with individuals who had an alternative underlying cause for their bronchiectasis, perhaps amplified by AATD. On the basis of our results, screening for AATD in patients who have bronchiectasis alone will likely not identify patients with severe AATD and other causes should first be sought. In the absence of any other cause, testing for AATD should then be considered. Testing for AATD in patients with bronchiectasis and co-existing emphysema, particularly when basal and panlobular in nature, should be undertaken according to the advice on testing for AATD in COPD guidelines for the investigation of patients with emphysema.
It would, therefore, seem that AATD testing in patients with bronchiectasis would be best reserved for patients with unexplained bronchiectasis in whom initial investigations have failed to identify a cause, and particularly in patients with co-existing emphysema. Whether the bronchiectasis in such patients would respond positively to AAT augmentation therapy remains unknown but, since bronchiectatic change is relatively common in AATD patients with emphysema, review of sequential scans in those who are or have been taking part in the placebo-controlled trials of augmentation with a focus on sequential bronchiectatic changes may prove informative.
References:
1 Caretto L, Morrison M, Donovan J, et al. Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis. Thorax 2020; 75:592-593.
2 Hill AT, Sullivan AL, Chalmers JD, et al. British thoracic Society guideline for
bronchiectasis in adults. Thorax 2019;74:1–69.
3 Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1
antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis 2016;3:668–82.
4 Cuvelier A, Muir JF, Hellot MF, et al. Distribution of alpha(1)-antitrypsin alleles in patients with bronchiectasis. Chest 2000;117:415–9.
5 Guest PJ, Hansell DM. High resolution computed tomography (HRCT) in emphysema associated with alpha-1 antitrypsin deficiency. Clin Radiol 1992; 45:260–266
6 King MA, Stone JA, Diaz PT, et al. a1-Antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology 1996; 199:137–141
7 Parr DG, Guest PG, Reynolds JH, et al. Prevalence and impact of bronchiectasis in
alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2007;176:1215–21.
I was surprised to see figure 2 in the paper by Stanojevic et al (1) on assessing paediatric FEV1 reproducibility as, on the face of it, the authors may have fallen into a notorious statistical trap. A change in any variable (FEV1, blood pressure etc) is ALWAYS negatively correlated with the initial value because if x is initial value then y-x is the change, so inevitably related. If as an example one uses two separate sets of 100 normally distributed random numbers, each set with mean 100 and standard deviation 12 to mimic percent FEV1 and plot the first set as X against the difference between the two sets (Y-X) it will show an entirely spurious negative correlation (r = -0.7) with typically around 50% of the ‘variance’ explained. Altman(2) instead has recommended plotting a change against their average as an improved way of assessing the true relationship and using identical values, the spurious correlation disappears.
1. Stanojevic S, Filipow N, Ratjen F. Paediatric reproducibility limits for the forced expiratory volume in 1 s. Thorax 2020;75:891-896.
2. Altman DG. From: Practical statistics for medical research. Chapman and Hall, Boca Raton, USA. 1999:282-285.
To the Editor
We thank Dr. Bhakta and colleagues for their interest in our article on the use of extracorporeal CO2 removal (ECCO2R) in patients with stable COPD and chronic hypercapnia (1).
Show MoreBhakta et al. pointed out the role of non invasive ventilation (NIV) to treat chronic hypercapnic respiratory failure by improving alveolar ventilation. The Authors additionally argued that, in evaluating the efficacy of ECCO2R in hypercapnic COPD stable patients who have failed NIV therapy, we only concentrated on the hypercapnic rather than the hypoxic aspects, pointing out that in this population symptomatic relief and long-term CO2 reduction cannot occur without improved oxygenation.
These points of discussion give us the opportunity to better explain the ECCO2R functioning and consequently the methodology of our study.
ECCO2R refers to an extracorporeal circuit that is able to selectively extract carbon dioxide from blood with little to no effect on oxygenation. Various ECCO2R systems are now available. In addition to PaCO2 baseline level, the ability of different ECCO2R devices to eliminate CO2 is dependent upon two important determinants: 1) the surface area available for gas exchange and 2) the blood flow rate (2). Moreover, the partial pressure gradient of the gas across the membrane can be obtained by using oxygen or air as sweep gas, according to Fick’s law of diffusion. Because in minimally invasive veno-venous ECCO 2 R systems the ratio of catheter...
Title: Extracorporeal CO2 removal (ECCO2R) in patients with stable COPD with chronic hypercapnia: applying the concept.
Show MorePradipta Bhakta, Antonio M. Esquinas, Brian O’Brien.
Authors:
1. Dr. Pradipta Bhakta (MD, MNAMS, FCAI, EDRA, EDIC)
Consultant,
Department of Anaesthesia and Intensive Care,
University Hospital Kerry, Tralee, Kerry, Ireland.
Phone: 00353894137596.
Email: bhaktadr@hotmail.com
2. Dr. Antonio M. Esquinas (PhD, MD)
Consultant,
Department of Intensive Care,
Hospital Morales Meseguer,
Murcia, Spain.
Phone: 0034609321966
Email: antmesquinas@gmail.com
3. Dr. Brian O’Brien [FCARCSI, FJFICMI, FCICM (ANZ)]
Consultant and Chair,
Department of Anaesthesia and Intensive Care,
Cork University Hospital, Cork, Ireland.
Mobile: 00353877931656
Email: drbobrien@hotmail.com
Authors and their role:
1. Dr. Pradipta Bhakta: Was involved analysis of the article, writing and editing the letter.
2. Dr. Antonio M. Esquinas: Was involved analysis of the article, writing and editing the letter.
3. Dr. Brian O’Brien: Was involved analysis of the article, writing and editing the letter.
Corresponding Author: Dr. Pradipta Bhakta,
Consultant,
Departm...
Dear Editors,
Show MoreThis journal published the BTS guidelines for the management of pulmonary nodules in August 2015 (1), leading to widespread evidence-based management of this common clinical problem. The use of the Herder score (2) to estimate or predict the likelihood of malignancy has since become routine in lung cancer MDMs around the country.
We therefore wish to highlight that the Herder prediction model was developed using the intensity of FDG uptake (absent, faint, moderate or intense) from the uncorrected PET images. However, as far as we are aware, lung cancer MDMs routinely assess the intensity of FDG uptake from the corrected images which is not in accordance with the original Herder model.
The use of uncorrected images in the original Herder study (2) to distinguish between uptake categories potentially alters the perceived evidence base of the recommendations in the BTS guidelines (1) to distinguish between faint and moderate uptake according to mediastinal blood pool given that this scale of uptake was not used in the original score, has not been validated and could mean we are not using the correct category in the risk model.
Furthermore, when considering the widespread use of the Herder score, it should be appreciated that it was formulated from patients scanned between 1997 and 2001. The Herder paper describes that “emission scans were acquired in a two-dimensional mode … and were reconstructed using ordered subset expectation maximisa...
We have read with interest the article by Taylor et al. concerning "the mechanism of lung development in the etiology of congenital malformations of the pulmonary airways in adults". The authors discussed the etiology of congenital malformations of the pulmonary airways, suggesting a partial modification of lung development with a potential risk of malignancy.
Although we generally agree with their assessment, there are some weaknesses in their work that we would like to highlight as well as some points on which we would like to propose an alternative point of view. Different transcription factors known to be involved in lung development have already been studied in CPAM. Two of them, SOX2 and SOX9 are described as important in the spatiotemporal branching development since the pseudoglandular stage [1, 2]. In CPAM, SOX2 is present in both CPAM types (1 and 2), but their expression differs between them [3]. In addition, previously published papers have shown persistent SOX2 expression in healthy lung, which is not the case in this paper. Unfortunately, Talyor et al present "adult" samples and not adjacent healthy. However, this is not sufficient to explain these differences and classical tissues from children should have been included to demonstrate this point. Moreover, a difference in the cells forming the two types of CPAM has already been described by immunohistochemistry and proteomic results. Nevertheless these points are not addressed in t...
Show MoreThe sneeze is depicted as horizontal, presumably for the camera. In a real sneeze, the head first tends to first tilt back, but during the actual sneeze, tends to point downwards. This means that large droplets tend to move toward the floor. Would have been nice to see a P2/N95 mask. Apart from that, a useful paper.
Dear Editor,
We agree with Koeckerling et al. that awake prone positioning, if proven beneficial, could provide a simple resource-conserving intervention that improves outcomes in COVID-19, especially in the resource-limited countries where even with mitigation strategies critical care bed demand is modelled to outstrip supply by a factor of 25.1,2
Currently, our knowledge about prone positioning is extrapolated from studies in non-awake, mechanically ventilated patients and so these proposed benefits remain theoretical.3-6
In addition to the various small-scale observational studies mentioned by Koeckerling et al., a recently published observational study of 24 awake COVID-19 patients concluded that awake prone positioning was well tolerated. However, the numbers were too small to confirm or refute any benefit in this population.7 Randomised control trial (RCT) is the gold standard for evidence in awake prone positioning in COVID-19 population. However, RCT will be a very difficult approach for this intervention due to the likelihood of a lack of equipoise amongst clinicians to recruit. Following national guidelines, many departments would implement this intervention as the standard of care. Awake prone positioning also appears to be a safe intervention in awake patients and may slow the respiratory deterioration in selected patients with COVID-19.1
Following the recent Intensive Care Society (ICS) guideline, clinicians within our institution ha...
Show MoreDear Editor,
Show MoreI read with interest Editorial by Wang et al. (1) regarding treatment of asthma in Covid-19 pandemic. It has been reported that allergic diseases, asthma, and chronic obstructive pulmonary disease were not risk factors for SARS-CoV-2 infection as shown in an earlier report from China (2). On the other hand, early data from Centre for Disease Control and Prevention (CDC) in the US suggest a higher rate of asthma in patients hospitalized for severe Covid-19 illness (3). On this background, patients with severe and uncontrolled asthma have also been included to be at increased risk of developing more severe Covid-19 according to CDC (3). It is however unclear whether increased risk is also relevant to the paediatric age group.
I agree with the authors that asthma control on a population scale may have improved due to reduced pollution, the use of face masks, better medication adherence and reduced smoking. However, these factors are of lesser importance in the paediatric age group. There is variability in the use of facial masks in different countries. It is most probably that lesser severe illness of Covid-19 in children due to the disease (asthma and respiratory allergy) itself that is offering some kind of protection. That protection seems to more than that being offered by adherence to medical treatment alone. Results from a recent cohort study indicate that children with asthma and allergies have reduced angiotensin-converting enzyme-2 (ACE2) gen...
We read with interest the article by Koeckerling et al. (1) regarding ‘Awake Prone
Show MorePositioning in COVID’. The authors have discussed the pros and cons of an
intervention that is being widely used during the COVID-19 pandemic. Although
we broadly agree with their assessment, there are some inaccuracies we would
like to point out as well as a few issues where we would like to offer an
alternative viewpoint:
1. Koeckerling and colleagues (1) quote that 78% of patients with severe
ARDS from a study by Ding et al (2) needed intubation. The original study
was performed prior to COVID-19 pandemic and reported that 55% of
patients with moderate to severe ARDS undergoing awake prone
positioning in conjunction with high flow nasal oxygen (HFNO) /non-
invasive ventilation (NIV) avoided intubation. All clinicians would agree that
invasive mechanical ventilation should not be delayed in the face of a
failing non-invasive intervention. The monitoring of the response to any
treatment is key to determining the appropriate management plan.
2. Koeckerling and colleagues report that CT scanning is essential to identify
which patients would benefit from awake prone positioning but this may not
be possible in view of the large numbers of patients. Gattinoni et al. do
describe different phenotypes based on CT appearances, but this is to
explain the pathophysiology of in different ph...
Caretto et al’s brief communication[1] shines some additional light on an unresolved question of the role of alpha-1 antitrypsin deficiency (AATD) screening in patients with bronchiectasis. The authors conclude that testing of an unselected UK population (presumably with a primary diagnosis of bronchiectasis) identifies severe AATD in less than 1% of cases and that routine screening does not significantly impact on clinical management. Whilst these conclusions may be broadly applicable, it may be advisable to qualify the recommendation with some further detail to avoid potential misinterpretation and the consequent complete avoidance of AATD testing in patients with bronchiectasis.
The study rationale originates from apparent conflicting recommendations of guidelines for bronchiectasis[2] and those for AATD[3]. It is stated by the authors that the latter advises AATD testing in all cases of bronchiectasis, whereas the guidelines (in recommendation 1c) in fact advocate testing in cases of ‘unexplained’ bronchiectasis. The use of the term ‘unexplained’ implies the use of a staged approach to the investigation of bronchiectasis with AATD testing reserved for a selected bronchiectasis population in which a diagnosis remains elusive despite clinically appropriate initial investigations.
Studies of bronchiectasis in AATD are few in number and relatively small in size. Nevertheless, there is some consistency in the findings. In their conclusions from a study of t...
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