Vitamin D could have potentiating effects on the innate and adaptive immune system (1). This would explain a potential defense effect against respiratory infections. Based on this, this vitamin has been linked to respiratory diseases such as COPD, asthma, respiratory infections and even lung cancer (2). In November 2020, our work team published the ACVID randomized clinical trial, and we have received a letter from Dr. Nobuyuki Horita asking us two questions about our results. In the first place, he lists a series of studies that show a great discrepancy in the results on quality of life, requesting our opinion on this discrepancy. Second, he asks for our opinion on the results of our work in terms of improving quality of life without an increase in lung function.
The authors continue to maintain that “some beneficial association was observed in the group of patients receiving vitamin D compared to the placebo group” in the studies analyzed in our article. In fact, in the VIDA research (3) the authors describe a small but significant association with the decrease in the dose of ciclesonide required to maintain asthma control in the vitamin D group. It is true that in this study the quality improvement Life is better in the control group, but this is a secondary objective. In the ViDiAs study (4) the authors found no significant differences in the reduction of asthma attacks or upper airway infections (coprimary outcomes), but, although they did not find clinical impr...
Vitamin D could have potentiating effects on the innate and adaptive immune system (1). This would explain a potential defense effect against respiratory infections. Based on this, this vitamin has been linked to respiratory diseases such as COPD, asthma, respiratory infections and even lung cancer (2). In November 2020, our work team published the ACVID randomized clinical trial, and we have received a letter from Dr. Nobuyuki Horita asking us two questions about our results. In the first place, he lists a series of studies that show a great discrepancy in the results on quality of life, requesting our opinion on this discrepancy. Second, he asks for our opinion on the results of our work in terms of improving quality of life without an increase in lung function.
The authors continue to maintain that “some beneficial association was observed in the group of patients receiving vitamin D compared to the placebo group” in the studies analyzed in our article. In fact, in the VIDA research (3) the authors describe a small but significant association with the decrease in the dose of ciclesonide required to maintain asthma control in the vitamin D group. It is true that in this study the quality improvement Life is better in the control group, but this is a secondary objective. In the ViDiAs study (4) the authors found no significant differences in the reduction of asthma attacks or upper airway infections (coprimary outcomes), but, although they did not find clinical improvement in quality of life, they did find a statistically significant difference between the arms. Quality of life was also a secondary objective of the ViDiAs study and discrepancies were found in the control of asthma measured with ACT that was worse in the group treated with vitamin D. In the study by Arshi et al (5) they observed an increase in pulmonary function tests (primary ednpoint). In the work of De Groot (6), a reduction in the percentage of eosinophils in induced sputum was found in patients with higher eosinophilic proportions in the sputum, as their primary objective. No changes in quality of life were observed. As Dr. Nobuyuki Horita indicates, there are discrepancies in different studies regarding the results on quality of life, as in the works of Rajanandh (7), Kerley (8) and Majak (9, 10). The ACVID study (11) was designed to investigate improvement in asthma control measured with ACT as a primary endpoint and quality of life measured with Mini-AQLQ was a secondary endpoint. A clinically and statistically significant improvement in asthma control was observed and, in addition, a statistically significant improvement in quality of life was found in patients receiving vitamin D versus placebo. We believe that the existing discrepancy in the results regarding vitamin D and asthma is due to the high variability in the design of the different studies with respect to the inclusion and exclusion criteria and the primary objectives of the studies. It would be necessary to standardize the design of the studies with clear primary objectives that later allow quality meta-analyzes to be carried out, with strong and credible results, to draw reliable and consistent conclusions that allow the asthma management guidelines to be changed.
Regarding the second question, in the ACVID study, the improvement in quality of life measured with MiniAQLQ was a secondary objective of the study, so the results must be analyzed with caution. A statistically significant improvement was observed in the group that received calcifediol supplementation compared to the group that received placebo with a difference of 0.70 (95% CI: 0.63 - 1.64; p = 0.01). The mean variation between the total initial and final scores in the Mini-AQLQ was 1.05 in the intervention group and -0.09 in the control group, p <0.001. However, no significant differences were observed in FEV1 between groups, nor in the initial and final difference in each group. We do not know for sure why this improvement in the quality of life of patients supplemented with vitamin D is due, but it is probably due to the different mechanisms by which this vitamin could influence asthma. Vitamin D could cause the modulation of different pro-inflammatory cytokines and would increase the production of antimicrobial peptides, such as cathelicidin and beta-defensin 2 (12). This vitamin has direct effects on T cells, reduces the production of IgE and increases the synthesis of IL-10 (13). Furthermore, vitamin D can reduce IL-17 responses in severe asthma, reducing bronchial hyperresponsiveness, remodeling, steroid resistance, and the synthesis of pro-inflammatory cytokines (14). In asthma, unlike COPD, lung function is variable and is usually preserved in patients in a stable phase, for this reason the patients in the ACVID study maintain their lung function unchanged during the study period. The improvement in quality of life could be due to the effects of vitamin D in reducing bronchial hyperresponsiveness, the synthesis of pro-inflammatory cytokines and resistance to steroids, which resulted in an improvement in asthma control and, therefore, therefore, in an improvement in the quality of life of asthmatic patients.
We thank Dr. Nobuyuki Horita for his interest in the ACVID study and hope we have responded to his concerns.
1. Garcia de Tena J, El Hachem Debek A, Hernandez Gutierrez C, Izquierdo Alonso JL. The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases. Arch Bronconeumol. 2014;50(5):179-84.
2. Herr C, Greulich T, Koczulla RA, Meyer S, Zakharkina T, Branscheidt M, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12:31.
3. Castro M, King TS, Kunselman SJ, Cabana MD, Denlinger L, Holguin F, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 2014;311(20):2083-91.
4. Martineau AR, MacLaughlin BD, Hooper RL, Barnes NC, Jolliffe DA, Greiller CL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax. 2015;70(5):451-7.
5. Arshi S, Fallahpour M, Nabavi M, Bemanian MH, Javad-Mousavi SA, Nojomi M, et al. The effects of vitamin D supplementation on airway functions in mild to moderate persistent asthma. Ann Allergy Asthma Immunol. 2014;113(4):404-9.
6. de Groot JC, van Roon EN, Storm H, Veeger NJ, Zwinderman AH, Hiemstra PS, et al. Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma. J Allergy Clin Immunol. 2015;135(3):670-5 e3.
7. Rajanandh MG, Nageswari AD, Prathiksha G. Effectiveness of vitamin D3 in severe persistent asthmatic patients: A double blind, randomized, clinical study. J Pharmacol Pharmacother. 2015;6(3):142-6.
8. Kerley CP, Hutchinson K, Cormican L, Faul J, Greally P, Coghlan D, et al. Vitamin D3 for uncontrolled childhood asthma: A pilot study. Pediatr Allergy Immunol. 2016;27(4):404-12.
9. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 2011;127(5):1294-6.
10. Majak P, Rychlik B, Stelmach I. The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children. Clin Exp Allergy. 2009;39(12):1830-41.
11. Andujar-Espinosa R, Salinero-Gonzalez L, Illan-Gomez F, Castilla-Martinez M, Hu-Yang C, Ruiz-Lopez FJ. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax. 2020.
12. Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965-74.
13. Hartmann B, Heine G, Babina M, Steinmeyer A, Zugel U, Radbruch A, et al. Targeting the vitamin D receptor inhibits the B cell-dependent allergic immune response. Allergy. 2011;66(4):540-8.
14. Nanzer AM, Chambers ES, Ryanna K, Richards DF, Black C, Timms PM, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1alpha,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol. 2013;132(2):297-304 e3.
Asthma and chronic obstructive pulmonary disease (COPD) are two major obstructive lung diseases. Many epidemiological and genetic research including ours suggested possible association between vitamin D (VitD) and these diseases.[1 2] A meta-analysis by Jolliffe in 2019 demonstrated that VitD supplementation surely reduced the frequency of exacerbations in COPD patients who had VitD deficiency.[3] Vitamin D is an attractive option especially in developing countries because some of currently used medications such as bronchodilators and biologics are pricy. Given such background, VitD supplementation has been expected to be a new strategy for asthmatic patients with VitD deficiency. Thus, we read a report by Dr. Andújar-Espinosa et al. with a great interest.[4] The ACVID trial, a well-designed triple-blind randomized controlled trial (RCT), indicated greater improvement of quality of life (QOL) measured by Asthma Control Test (ACT) score as the primary endpoint, in the calcifediol arm compared to the placebo arm. Nonetheless, we have two concerns for this trial.
First, there was a considerable discrepancy about the efficacy with previous reports. Inconsistency is a reason to degrade the quality of evidence.[5] Authors mentioned that "some beneficial association was observed in the group of patients receiving VitD compared with the placebo group" in all previous studies.[4] However, very limited data support the QOL improvement observed in ACVID trial. Dr. And...
Asthma and chronic obstructive pulmonary disease (COPD) are two major obstructive lung diseases. Many epidemiological and genetic research including ours suggested possible association between vitamin D (VitD) and these diseases.[1 2] A meta-analysis by Jolliffe in 2019 demonstrated that VitD supplementation surely reduced the frequency of exacerbations in COPD patients who had VitD deficiency.[3] Vitamin D is an attractive option especially in developing countries because some of currently used medications such as bronchodilators and biologics are pricy. Given such background, VitD supplementation has been expected to be a new strategy for asthmatic patients with VitD deficiency. Thus, we read a report by Dr. Andújar-Espinosa et al. with a great interest.[4] The ACVID trial, a well-designed triple-blind randomized controlled trial (RCT), indicated greater improvement of quality of life (QOL) measured by Asthma Control Test (ACT) score as the primary endpoint, in the calcifediol arm compared to the placebo arm. Nonetheless, we have two concerns for this trial.
First, there was a considerable discrepancy about the efficacy with previous reports. Inconsistency is a reason to degrade the quality of evidence.[5] Authors mentioned that "some beneficial association was observed in the group of patients receiving VitD compared with the placebo group" in all previous studies.[4] However, very limited data support the QOL improvement observed in ACVID trial. Dr. Andújar-Espinosa et al. misleadingly mentioned that ViDiAs researchers "found a significant association in improving quality of life, measured with the St George Respiratory Questionnaire (SGRQ).4" In fact, ViDiAs researchers wrote "of 16 secondary outcomes investigated, only one, respiratory QOL, as measured by the SGRQ, showed a statistically significant difference between arms, but this was just less than the 4-point minimum clinically important difference for this instrument.6" In the same trial, VitD supplementation led to 0.3 points poorer improvement of ACT score than placebo.[6] The QOL change from the baseline in the other previous studies are below. The largest RCT, VIDA, with 408 patients with baseline VitD < 30 ng/mL showed slightly better change of QOL in control arm.[7] Another large trial with 161 cases by Rajanandh revealed 3.1 points greater improvement of SGRQ total score in placebo group.8 Groot et al. randomized and analyzed 44 asthmatic patients with serum VitD below 100 ng/mL and detected no difference of QOL change.[9] Kerley et al. evaluated 39 children without requesting specific VitD level for inclusion and found placebo-favored QOL improvement in whole cohort and low VitD ( <50 ng/mL) cohort.[10] Majak et al. published two reports comparing steroid alone versus steroid plus VitD3 for patients with any serum VitD level.[11 12] These reports showed insignificant trends toward opposite directions with each other.[11 12] In short, although ACVID trial revealed drastic improvement of ACT score, no other studies achieved substantial benefit in QOL. Rather, many trials showed non-significant trend toward worse QOL in VitD arm. We would like to know what causes this discrepancy.
The second is the lack of improvement of forced expiratory volume in one second (FEV1), the key measurement in asthma trials. Table 3 of the report by Dr. Andújar-Espinosa et al. implied that patients who were treated with calcifediol had 203 mL larger FEV1.4 However, this difference would disappear after adjusting baseline difference, 208 mL better in calcifediol arm.4 To our understanding, medical therapy improves QOL of patients with asthma mainly by resolving bronchial obstruction assessable by FEV1. We would like to ask Dr. Andújar-Espinosa how VitD improved the QOL without better FEV1 improvement.[4]
Regardless of our concerns, we are grateful for the authors because they provided the most up-to-date information for VitD supplementation in asthmatic patients.[4]
References
1. Herr C, Greulich T, Koczulla RA, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respiratory Research 2011;12.
2. Horita N, Miyazawa N, Tomaru K, et al. Vitamin D binding protein genotype variants and risk of chronic obstructive pulmonary disease: a meta-analysis. Respirology (Carlton, Vic) 2015;20(2):219-25.
3. Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019;74(4):337-45.
4. Andújar-Espinosa R, Salinero-González L, Illán-Gómez F, et al. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax 2020.
5. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. Journal of clinical epidemiology 2011;64(12):1294-302.
6. Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70(5):451-7.
7. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. Jama 2014;311(20):2083-91.
8. Rajanandh MG, Nageswari AD, Prathiksha G. Effectiveness of vitamin D3 in severe persistent asthmatic patients: A double blind, randomized, clinical study. Journal of pharmacology & pharmacotherapeutics 2015;6(3):142-6.
9. de Groot JC, van Roon EN, Storm H, et al. Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma. The Journal of allergy and clinical immunology 2015;135(3):670-5.e3.
10. Kerley CP, Hutchinson K, Cormican L, et al. Vitamin D3 for uncontrolled childhood asthma: A pilot study. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 2016;27(4):404-12.
11. Majak P, Olszowiec-Chlebna M, Smejda K, et al. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. The Journal of allergy and clinical immunology 2011;127(5):1294-6.
12. Majak P, Rychlik B, Stelmach I. The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2009;39(12):1830-41.
Short comment to the article:
Campisi A, Poletti V, Ciarrocchi AP, et al. (2020). Tension pneumomediastinum in patients with COVID-19. Thorax 2020; 75:1130-1131.
Igor Klepikov*
The authors describe a relatively rare complication that usually accompanies various diseases of the respiratory system and can significantly worsen the condition of patients. The fact that this complication occurs not only in patients with lung ventilation problems, but even in women in labor (1) suggests that an important trigger factor for this phenomenon is sudden attacks of increased intra-bronchial pressure. Such a sudden increase in air pressure in a confined space, according to Pascal's law (2), spreads evenly in all directions and can create an air flow to the surrounding tissues, damaging the weakest or previously damaged tissues.
However, free air in the mediastinum has a clear anatomical localization, and its appearance is due to tissue damage in the area that has a common anatomical space and a free communication with the Central intra-thoracic space. In this regard, the mechanism of air penetration into the mediastinal fiber, which is described by the authors (3), automatically borrowing it from the assumptions of other researchers (4), looks, from my point of view, fantastic, far from real conditions.
First of all, there is no objective evidence that air enters the mediastinum through the perivascular spaces as a result of damage...
Short comment to the article:
Campisi A, Poletti V, Ciarrocchi AP, et al. (2020). Tension pneumomediastinum in patients with COVID-19. Thorax 2020; 75:1130-1131.
Igor Klepikov*
The authors describe a relatively rare complication that usually accompanies various diseases of the respiratory system and can significantly worsen the condition of patients. The fact that this complication occurs not only in patients with lung ventilation problems, but even in women in labor (1) suggests that an important trigger factor for this phenomenon is sudden attacks of increased intra-bronchial pressure. Such a sudden increase in air pressure in a confined space, according to Pascal's law (2), spreads evenly in all directions and can create an air flow to the surrounding tissues, damaging the weakest or previously damaged tissues.
However, free air in the mediastinum has a clear anatomical localization, and its appearance is due to tissue damage in the area that has a common anatomical space and a free communication with the Central intra-thoracic space. In this regard, the mechanism of air penetration into the mediastinal fiber, which is described by the authors (3), automatically borrowing it from the assumptions of other researchers (4), looks, from my point of view, fantastic, far from real conditions.
First of all, there is no objective evidence that air enters the mediastinum through the perivascular spaces as a result of damage to the tissue barriers in the alveolar parts of the lungs. This path of air propagation should not just be visible, but very clearly distinguishable on x-rays and tomograms. Before entering the mediastinum, the air must create clusters around the vessels with significant tissue stratification. It can't enter the mediastinum through the perivascular spaces without leaving any traces in them, right? In addition, the mediastinum is the next stage of air propagation and should contain less of it than the tissues from which it comes. This is simple physics, and the predominance of air in the mediastinum over its volume in the lung tissue can only be in the presence of a valve mechanism. Нowever, the presence of free air at the point of tissue damage should be constant, regardless of the further conditions of its spread.
Subcutaneous emphysema cannot "hide" the macromorphology of the organ itself on lung tomograms, in contrast to the opinion of the authors of the publication (3). Everything looks the opposite if you look at the illustrations given in the article. Even on tomograms of lungs with a large amount of air in the mediastinum, there are no hints of its presence in perivascular tissues (3-5). In fact, the localization of the cause of pneumomediastinum has a purely anatomical explanation. The mediastinal cavity surrounds most of the trachea and the proximal parts of the main bronchi and has no other anatomical connections with structures located laterally from the mediastinal pleura. Therefore, tissue defects in the form of small cracks through which air enters the mediastinum can be located in the initial sections of the main bronchi or in the trachea.
In vivo diagnosis of such microtraumas remains, as a rule, unrealized, and for post-mortem determination of the localization of microdefect, a special method of checking the airway tightness is required. To do this, during the autopsy, the lung complex is submerged under water and air is pumped into it through a cannula or endotracheal tube using a breathing nozzle. The area of the detected defect can be subjected to targeted histological examination. This technique was used for post-mortem diagnosis of the source of pneumomediastinum in previous years by the author of these lines.
The need to clarify the mechanism of occurrence of pneumomediastinum is of great practical importance, since in the case of intra-thoracic compression syndrome, patients need immediate help. Such assistance can be used not only for mediastinal drainage, but also for video-assisted thoracoscopy and even thoracotomy (4). If the source of the complication is located directly in the area of increased intra-thoracic pressure, why should this area be approached in a roundabout way? The authors ' observation (3) demonstrates the shortest path to the source of the problem and the less traumatic nature of high-performance management.
By the way, pneumopericardium, which is classified as a pathology requiring differential diagnosis with pneumomediastinum (4), has a very similar mechanism of development. The source of free air in the pericardium is micro-damage to the tracheal bifurcation area and the initial sections of the main bronchi, which are anatomically partially located in the cavity of the heart jacket. This complication is also not accompanied by any changes in other parts of the chest, which could be considered as a source of air supply to the pericardium.
Bibliography
1.Hamman L. Spontaneous mediastinal emphysema. Bull Johns Hopkins Hosp 1939; 64:1-21.
2.https://en.wikipedia.org/wiki/Pascal%27s_law
3. Campisi A, Poletti V, Ciarrocchi AP, et al. (2020). Tension pneumomediastinum in patients with COVID-19. Thorax 2020; 75:1130-1131.
4. Kouritas VK, Papagiannopoulos K, Lazaridis G, et al.2015). Рneumomediastinum. J Thorac Dis, 2015;7:S44–9.
5. Zhou C, Gao C, Xie Y, et al. (2020). COVID-19 with spontaneous pneumomediastinum. Lancet Infect Dis, 2020;20:510.
*MD, professor,retired
E-mail address: igor.klepikov@yahoo.com
We would like to thank Dr. Klepikov for his interest in our article [1], despite his dispute of the pathophysiology we presented. As it may be clearly understood from the article, our purpose was to present a relatively rare clinical case represented by a tension pneumomediastinum and not to evaluate its underlying pathophysiological mechanism. In our experience, this clinical scenario is extremely rare to face in a general thoracic surgery unit, but it has become more frequent in the last year due to SARS-CoV2 pandemic and the frequent use of high volume invasive ventilation in these patients [2,3]. The article [1] focuses on the most important aspects of the clinical case from the mechanical ventilation to the surgical therapy briefly mentioning the most likely mechanism of the origin of pneumomediastinum according to the peer-reviewed literature at hand [3,4]. As one can imagine an extensive and in-depth analysis of the pathophysiology of pneumomediastinum would be a difficult task to undertake in an article with a 500-word limit which aims to present our treatment of the condition.
According to literature [2,3,4], different hypotheses have been proposed to explain the pathophysiology underlying spontaneous pneumomediastinum, but the most accepted one has been described by Macklin and Macklin [5]. The presence of a pressure gradient between the alveoli and the lung interstitium results in alveolar rupture and, if the pressure gradient is mainta...
We would like to thank Dr. Klepikov for his interest in our article [1], despite his dispute of the pathophysiology we presented. As it may be clearly understood from the article, our purpose was to present a relatively rare clinical case represented by a tension pneumomediastinum and not to evaluate its underlying pathophysiological mechanism. In our experience, this clinical scenario is extremely rare to face in a general thoracic surgery unit, but it has become more frequent in the last year due to SARS-CoV2 pandemic and the frequent use of high volume invasive ventilation in these patients [2,3]. The article [1] focuses on the most important aspects of the clinical case from the mechanical ventilation to the surgical therapy briefly mentioning the most likely mechanism of the origin of pneumomediastinum according to the peer-reviewed literature at hand [3,4]. As one can imagine an extensive and in-depth analysis of the pathophysiology of pneumomediastinum would be a difficult task to undertake in an article with a 500-word limit which aims to present our treatment of the condition.
According to literature [2,3,4], different hypotheses have been proposed to explain the pathophysiology underlying spontaneous pneumomediastinum, but the most accepted one has been described by Macklin and Macklin [5]. The presence of a pressure gradient between the alveoli and the lung interstitium results in alveolar rupture and, if the pressure gradient is maintained, the air tracks along the vascular sheaths to the mediastinum [5]. In the case of SARS-CoV2 pneumonia, the virus alters the alveolar membrane integrity as it infects both type I and II pneumocytes [6], increasing the probability of a spontaneous pneumomediastinum [3]. This coupled with high volume invasive ventilation further increases the risk of pneumomediastinum.
Dr. Klepikov describes a post-mortem method to identify the presence of microdefects of the major tracheobronchial tree. The simple method is similar to any in-vivo air leak test a thoracic surgeon performs during lung and tracheal surgery, but it has not been published or demonstrated to be a potential explanation for the pathophysiology of spontaneous pneumomediastinum. If so, the Macklin effect would not have been considered by us. Furthermore, Dr. Klepikov fails to produce any peer-reviewed manuscripts or sources as evidence for his critique.
We wholeheartedly agree with Dr. Klepikov’s statement that it is essential in clinical practice to understand the basic mechanism of the pneumomediastinum but we would like to stress that in our daily practice this clinical scenario is an emergency. In fact, the patients are often hemodynamically unstable and the necessity to solve the problem is far more important than being “less traumatic''.
The mechanism of pneumopericardium is beyond the scope of this article, thus it was not discussed.
References
1) Campisi A, Poletti V, Ciarrocchi AP, Salvi M, Stella F. Tension pneumomediastinum in patients with COVID-19. Thorax. 2020 Dec;75(12):1130-1131.
2) Kolani S, Houari N, Haloua M, et al. Spontaneous pneumomediastinum occurring in the SARS-COV-2 infection. IDCases. 2020 May 11;21:e00806.
3) Lemmers DHL, Abu Hilal M, Bnà C, Prezioso C, Cavallo E, Nencini N, Crisci S, Fusina F, Natalini G. Pneumomediastinum and subcutaneous emphysema in COVID-19: barotrauma or lung frailty? ERJ Open Res. 2020 Nov 16;6(4):00385-2020. doi: 10.1183/23120541.00385-2020.
4) Macia I., Moya J., Ramos R. Spontaneous pneumomediastinum: 41 cases. Eur J Cardiothorac Surg. 2007;31:1110–1114.
5 )Macklin M.T., Macklin C.C. Malignant interstitial emphysema of the lungs and mediastinum as an important occult complication in many respiratory diseases and other conditions: interpretation of the clinical literature in the light of laboratory experiment. Medicine. 1944;23:281–358.
We would like to thank Dr. Rosenthal for his comment on our research. Dr. Rosenthal highlights that a change in FEV will inevitably be negatively correlated with the initial value; otherwise known as regression to the mean. One important distinction with our work is that we calculated the conditional change score based on z-scores and thus demonstrate the changes that are greater than that predicted by regression to the mean. By calculating the conditional change using z-scores we change the scale which is used and account for this fallacy. Reporting the differences using Bland-Alman is an alternative approach but will be limited to analysis of fixed time-intervals and if the variability is constant across age and time.
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.
Vitamin D could have potentiating effects on the innate and adaptive immune system (1). This would explain a potential defense effect against respiratory infections. Based on this, this vitamin has been linked to respiratory diseases such as COPD, asthma, respiratory infections and even lung cancer (2). In November 2020, our work team published the ACVID randomized clinical trial, and we have received a letter from Dr. Nobuyuki Horita asking us two questions about our results. In the first place, he lists a series of studies that show a great discrepancy in the results on quality of life, requesting our opinion on this discrepancy. Second, he asks for our opinion on the results of our work in terms of improving quality of life without an increase in lung function.
Show MoreThe authors continue to maintain that “some beneficial association was observed in the group of patients receiving vitamin D compared to the placebo group” in the studies analyzed in our article. In fact, in the VIDA research (3) the authors describe a small but significant association with the decrease in the dose of ciclesonide required to maintain asthma control in the vitamin D group. It is true that in this study the quality improvement Life is better in the control group, but this is a secondary objective. In the ViDiAs study (4) the authors found no significant differences in the reduction of asthma attacks or upper airway infections (coprimary outcomes), but, although they did not find clinical impr...
Asthma and chronic obstructive pulmonary disease (COPD) are two major obstructive lung diseases. Many epidemiological and genetic research including ours suggested possible association between vitamin D (VitD) and these diseases.[1 2] A meta-analysis by Jolliffe in 2019 demonstrated that VitD supplementation surely reduced the frequency of exacerbations in COPD patients who had VitD deficiency.[3] Vitamin D is an attractive option especially in developing countries because some of currently used medications such as bronchodilators and biologics are pricy. Given such background, VitD supplementation has been expected to be a new strategy for asthmatic patients with VitD deficiency. Thus, we read a report by Dr. Andújar-Espinosa et al. with a great interest.[4] The ACVID trial, a well-designed triple-blind randomized controlled trial (RCT), indicated greater improvement of quality of life (QOL) measured by Asthma Control Test (ACT) score as the primary endpoint, in the calcifediol arm compared to the placebo arm. Nonetheless, we have two concerns for this trial.
Show MoreFirst, there was a considerable discrepancy about the efficacy with previous reports. Inconsistency is a reason to degrade the quality of evidence.[5] Authors mentioned that "some beneficial association was observed in the group of patients receiving VitD compared with the placebo group" in all previous studies.[4] However, very limited data support the QOL improvement observed in ACVID trial. Dr. And...
Short comment to the article:
Show MoreCampisi A, Poletti V, Ciarrocchi AP, et al. (2020). Tension pneumomediastinum in patients with COVID-19. Thorax 2020; 75:1130-1131.
Igor Klepikov*
The authors describe a relatively rare complication that usually accompanies various diseases of the respiratory system and can significantly worsen the condition of patients. The fact that this complication occurs not only in patients with lung ventilation problems, but even in women in labor (1) suggests that an important trigger factor for this phenomenon is sudden attacks of increased intra-bronchial pressure. Such a sudden increase in air pressure in a confined space, according to Pascal's law (2), spreads evenly in all directions and can create an air flow to the surrounding tissues, damaging the weakest or previously damaged tissues.
However, free air in the mediastinum has a clear anatomical localization, and its appearance is due to tissue damage in the area that has a common anatomical space and a free communication with the Central intra-thoracic space. In this regard, the mechanism of air penetration into the mediastinal fiber, which is described by the authors (3), automatically borrowing it from the assumptions of other researchers (4), looks, from my point of view, fantastic, far from real conditions.
First of all, there is no objective evidence that air enters the mediastinum through the perivascular spaces as a result of damage...
Dear Editor,
We would like to thank Dr. Klepikov for his interest in our article [1], despite his dispute of the pathophysiology we presented. As it may be clearly understood from the article, our purpose was to present a relatively rare clinical case represented by a tension pneumomediastinum and not to evaluate its underlying pathophysiological mechanism. In our experience, this clinical scenario is extremely rare to face in a general thoracic surgery unit, but it has become more frequent in the last year due to SARS-CoV2 pandemic and the frequent use of high volume invasive ventilation in these patients [2,3]. The article [1] focuses on the most important aspects of the clinical case from the mechanical ventilation to the surgical therapy briefly mentioning the most likely mechanism of the origin of pneumomediastinum according to the peer-reviewed literature at hand [3,4]. As one can imagine an extensive and in-depth analysis of the pathophysiology of pneumomediastinum would be a difficult task to undertake in an article with a 500-word limit which aims to present our treatment of the condition.
Show MoreAccording to literature [2,3,4], different hypotheses have been proposed to explain the pathophysiology underlying spontaneous pneumomediastinum, but the most accepted one has been described by Macklin and Macklin [5]. The presence of a pressure gradient between the alveoli and the lung interstitium results in alveolar rupture and, if the pressure gradient is mainta...
We would like to thank Dr. Rosenthal for his comment on our research. Dr. Rosenthal highlights that a change in FEV will inevitably be negatively correlated with the initial value; otherwise known as regression to the mean. One important distinction with our work is that we calculated the conditional change score based on z-scores and thus demonstrate the changes that are greater than that predicted by regression to the mean. By calculating the conditional change using z-scores we change the scale which is used and account for this fallacy. Reporting the differences using Bland-Alman is an alternative approach but will be limited to analysis of fixed time-intervals and if the variability is constant across age and time.
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...
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