With great interest we have read the study by Deshayes et al. The authors present two cases of silvernitrate (AgNO3) aspiration in laryngectomized patients.
1) In both cases the applicator tip broke off.
2) The authors conclude that treatment should comprise oral antibiotics and one should refrain from bronchial washing with sodium chloride solution.
With this response we would like to reply to both points addressed above.
1.
Five years ago we were confronted with the aspiration of an AgNO3 applicator tip in a laryngectomized patient. After the incident we analyzed the case to prevent future AgNO3 applicator tip aspiration. The AgNO3 pencil, used in both our case and the cases in the current article, is specifically designed to treat dermal lesions like verruca which requires repeated use. The pencil therefore contains a relatively large volume of AgNO3. AgNO3 is a brittle substance. When the pencil is used with a little too much pressure there is risk for the tip to break, and when used in a tracheostomy, there is risk for aspiration.
Our case led us to immediately stop using the AgNO3 pencils for treatment of granulation tissue in a tracheostomy. We strongly recommend the use of disposable AgNO3 cutaneous sticks for the treatment of granulation tissue around a tracheostomy. The disposable sticks contains less volume of AgNO3. Moreover, the stick is easier to use in narrow spaces like a tracheostomy.
2.
Aspiration of AgNO3 i...
With great interest we have read the study by Deshayes et al. The authors present two cases of silvernitrate (AgNO3) aspiration in laryngectomized patients.
1) In both cases the applicator tip broke off.
2) The authors conclude that treatment should comprise oral antibiotics and one should refrain from bronchial washing with sodium chloride solution.
With this response we would like to reply to both points addressed above.
1.
Five years ago we were confronted with the aspiration of an AgNO3 applicator tip in a laryngectomized patient. After the incident we analyzed the case to prevent future AgNO3 applicator tip aspiration. The AgNO3 pencil, used in both our case and the cases in the current article, is specifically designed to treat dermal lesions like verruca which requires repeated use. The pencil therefore contains a relatively large volume of AgNO3. AgNO3 is a brittle substance. When the pencil is used with a little too much pressure there is risk for the tip to break, and when used in a tracheostomy, there is risk for aspiration.
Our case led us to immediately stop using the AgNO3 pencils for treatment of granulation tissue in a tracheostomy. We strongly recommend the use of disposable AgNO3 cutaneous sticks for the treatment of granulation tissue around a tracheostomy. The disposable sticks contains less volume of AgNO3. Moreover, the stick is easier to use in narrow spaces like a tracheostomy.
2.
Aspiration of AgNO3 is rare, so there is no clinical evidence that proves for or against bronchial washing with sodium chloride solution. From a theoretical perspective there is an argument to advise bronchial washing with sodium chloride solution after AgNO3 aspiration. As previously concluded, AgNO3 is activated when it is dissolved in water. AgNO3 is neutralized when in contact with sodium chloride solution (AgNO3 → AgCl + NaNO3). Correspondingly, the manufacturer advices to repeatedly wash the stomach with sodium chloride solution after AgNO3 ingestion. The authors conclude that one should not wash with sodium chloride solution due to the risk for spread of AgNO3 and potential secondary stenosis. Corresponding to the manufacturer information AgNO3 is neutralized when dissolved in sodium chloride solution. Based on theory and manufacturer information we advise thorough bronchial washing with sodium chloride solution after AgNO3 aspiration.
We read with interest the recent study by our colleagues Tan et al (1) which reported the introduction of public health measures during the pandemic, such as social distancing and universal mask wearing, were observed to coincide with a marked reduction in transmission of other circulating respiratory viral infections. They reported a reduction in hospital admissions with acute exacerbation of COPD (AECOPD) by over 50% during the six month period of the pandemic from February to June 2020. They supported this observation with microbiological data showing a significant reduction in PCR-positive respiratory viral infections compared to the pre-pandemic era.
Ireland has the highest rate of hospitalisations for AECOPD in all OECD Countries (2). The first case of COVID-19 in the Republic of Ireland was reported on 29/02/2020 and stringent public health measures were introduced in mid-March to combat the spread (3).
We wish to describe our experiences of hospital admission with AECOPD during the first wave of the pandemic in a tertiary referral hospital in the West of Ireland. In our clinical practice, we noticed a reduction in patients admitted with COPD exacerbations at the beginning of the pandemic. We aimed to evaluate the impact of these infection control measures on our COPD population.
We conducted a retrospective cohort study of electronic health care records of patients who were hospitalised with a primary diagnosis of AECOPD over the four-month per...
We read with interest the recent study by our colleagues Tan et al (1) which reported the introduction of public health measures during the pandemic, such as social distancing and universal mask wearing, were observed to coincide with a marked reduction in transmission of other circulating respiratory viral infections. They reported a reduction in hospital admissions with acute exacerbation of COPD (AECOPD) by over 50% during the six month period of the pandemic from February to June 2020. They supported this observation with microbiological data showing a significant reduction in PCR-positive respiratory viral infections compared to the pre-pandemic era.
Ireland has the highest rate of hospitalisations for AECOPD in all OECD Countries (2). The first case of COVID-19 in the Republic of Ireland was reported on 29/02/2020 and stringent public health measures were introduced in mid-March to combat the spread (3).
We wish to describe our experiences of hospital admission with AECOPD during the first wave of the pandemic in a tertiary referral hospital in the West of Ireland. In our clinical practice, we noticed a reduction in patients admitted with COPD exacerbations at the beginning of the pandemic. We aimed to evaluate the impact of these infection control measures on our COPD population.
We conducted a retrospective cohort study of electronic health care records of patients who were hospitalised with a primary diagnosis of AECOPD over the four-month period of 01/03/2020 to 30/06/2020 which corresponded to the period where the strictest public health guidelines were in place. We compared this period to the same four-month period in the previous year as a control group. The primary outcome was the number of admissions with a primary diagnosis of AECOPD. The secondary outcomes we assessed were: a) the severity of AECOPD as determined by DECAF score (3) b) length of stay c) acute in-hospital mortality.
Overall, there were 123 hospitalisations with AECOPD in the 2020 cohort compared with 150 hospitalisations the previous year. This corresponds to a 18% reduction in hospital admissions. Table 1 and Table 2 below display the results. However, when subgroup analysis by month was performed, this reduction was primarily driven by a significant reduction in admissions during March 2020 (20 vs 42, p=0.02). There was no significant difference between the following three months between the pandemic and control period. Male patients accounted for just over 50% in both groups. Those in the pandemic group were significantly older, median 76 years (IQR 70-84) compared with 73.5 years (IQR 67-80), p<0.01.
We calculated DECAF scores (4) as a measure of the severity of exacerbations and allow an objective comparison between groups. There was no statistical or clinical difference in the mean DECAF scores between groups, 1.94 (+/- 1.34) and 1.73 (+/-1.25) nor the proportion of patients presenting with a DECAF of > 3 indicating a severe exacerbation. In the pandemic group 5.7% (n=7) died in hospital compared with 4.7% (n=7) in the control group. This was not significant and in-hospital mortality was slightly lower than other published studies on mortality in AECOPD (5,6) although there are many factors that can influence in-hospital mortality. There was no difference in median length of stay of those discharged, which was approximately 7 days in both groups. Interestingly, on subgroup analysis, more patients died during May 2020 than the previous May 2019 (10% (n=2) versus 0% (n=0), p <0.04) although the absolute numbers are very small.
Our experience with AECOPD during the pandemic period contrasts with the experiences of Tan et al, and indeed of a previous Hong Kong study which noted a 44% reduction in AECOPD during the pandemic period (7). While there was a reduction of 18% overall this is of smaller magnitude than the above studies of similar duration. Furthermore, the reduction is accounted for almost entirely by a dramatic reduction in admissions during the month of March alone which was the beginning of the lockdown period in Ireland, followed by a restoration of admissions to levels comparable to the previous year.
Although there were no detectable differences in DECAF scores of patients admitted, the overall trend of admissions along with the proportional increase in mortality during March suggests that hospital avoidance may account for the temporary but dramatic reduction in admissions. There have been well-publicised concerns regarding patients delaying seeking hospital care for emergencies such as myocardial infarctions and strokes, due to fears of contracting COVID-19 (8). Thus, it is plausible that patients with COPD who had mild to moderate exacerbations may have sought assistance from primary care facilities in the first instance resulting in a smaller but sicker cohort of patients presenting to hospital with a corresponding mortality bias.
We agree that reduced viral transmission is certainly an important factor in reducing AECOPD and the reports on reduction in influenza rates support Tan et al’s viral PCR studies (1,9). Anti-viral therapies merit an increased research focus to target therapeutic options. However, if viral reduction accounted in part for the reduction in AECOPD in our patient population, it appears to have been a transient phenomenon at most. Conversely and fortuitously, our patients appeared to have benefited from the extremely low levels of COVID-19 during the first wave of the pandemic in our predominantly rural catchment area. Only one patient tested positive for SARS-COV-2 during the study period and recovered fully.
In summary, we feel that our contrasting results to Tan et al are of interest and merit discussion. Our findings are plausible explained by differences in public support and adherence to universal mask wearing during the first wave of the pandemic and public attitudes to the risk of nosocomial transmission of COVID-19.
References
1. Tan JY, Conceicao EP, Wee LE, Sim XY, Venkatachalam I. COVID-19 public health measures: a reduction in hospital admissions for COPD exacerbations. Thorax. 2020 Dec 3.
2. National Clinical Effectiveness Committee. National Clinical Guideline: Management of Chronic Obstructive Pulmonary Disease (COPD) Version 5.0. Department of Health. July 2020
3. Department of Health. Statement from National Public Health Emergency Team- 29 February 2020. February 2020. Available at gov.ie - Statement from the National Public Health Emergency Team - Saturday 29 February (www.gov.ie)
4. Steer J, Gibson J, Bourke SC. The DECAF Score: predicting hospital mortality in exacerbations of chronic obstructive pulmonary disease. Thorax. 2012 Nov 1;67(11):970-6.
5. Connors Jr AF, Dawson NV, Thomas C, Harrell Jr FE, Desbiens N, Fulkerson WJ, Kussin P, Bellamy P, Goldman L, Knaus WA. 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). American journal of respiratory and critical care medicine. 1996 Oct;154(4):959-67.
6. Gunen H, Hacievliyagil SS, Kosar F, Mutlu LC, Gulbas G, Pehlivan E, Sahin I, Kizkin O. Factors affecting survival of hospitalised patients with COPD. European Respiratory Journal. 2005 Aug 1;26(2):234-41.
7. Chan KP, Ma TF, Kwok WC et al. Significant reduction in hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in Hong Kong during coronavirus disease 2019 pandemic. Respiratory Medicine. 2020 Jul 12:106085.
8. Lange SJ, Ritchey MD, Goodman AB et al. Potential indirect effects of the COVID-19 pandemic on use of emergency departments for acute life-threatening conditions—United States, January–May 2020. MMWR Morb Mortal Wkly Rep 2020 Jun 26;69(25):795.
9. Soo RJ, Chiew CJ, Ma S et al. Decreased influenza incidence under COVID-19 control measures, Singapore. Emerg Infect Dis. 2020 Aug;26(8):1933.
2020 2019 P value
No of AECOPD 123 150
Male-N (%) 66 (53.7%) 77 (51.3%) P=0.383
Age- Median 76 (70-84) 73.5 (67-80) P <0.01
March (N) 20 42 0.02
April (N) 38 40 0.44
May (N) 33 32 0.29
June (N) 32 36 0.70
Table 2. Clinical Presentation -DECAF score of patients
2020 (n=123) 2019 (n=150) P value
DECAF
Mean ±SD 1.94 (+/- 1.34) 1.73 (+/- 1.25) 0.182
DECAF ≥3: N (%) 32 (26%) 41 (27.3%) 0.81
Clinical Parameters of DECAF score N (%)
Dyspnoea mMRC 5a/5b 70 82 0.711
Dyspnoea mMRC 5a 46 68 0.187
Dyspnoea mMRC 5b 24 14 0.015
Eosinopenia 54 63 0.749
Consolidation 38 52 0.509
Atrial fibrillation 40 34 0.069
Acidaemia 13 16 0.97
Outcomes
LOS (days) Median 6.5 (4-11) 7 (4-11) 0.98
Deaths 7 (5.7%) 7 (4.7%) 0.704
Deaths March 2 (10%) 0 (0%) 0.037
Deaths April 1 (2.6%) 1 (2.5%) 0.97
Deaths May 2 (6%) 3 (9.4%) 0.62
Deaths June 2 (6.3%) 3 (8.3%) 0.74
The paper by Hopkinson et al (1) provides unique and important data on smoking prevalence and COVID-19 symptoms, but their conclusion does not reflect the data well. The authors conclude “these data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19”. The study includes over 150,000 people with self-reported COVID-19 symptoms and over two million without such symptoms. It also includes data on over 25,000 people who were tested for SARS-CoV-2 and their test results. Based on our analysis of these more relevant data, we interpret the study differently. Our conclusion would be “these data are consistent with smokers having an increased risk of symptoms such as cough and breathlessness, but a decreased risk of having SARS-CoV-2 infection”.
The difficulty in interpreting these results is that both symptoms and testing are likely colliders in a causal model of smoking and COVID-19. The data reported on SARS-CoV-2 test results make it possible to compare smoking prevalence by age-group and sex in three groups: those who tested positive for SARS-CoV-2 (n=7,123); those who tested negative (n=16,765); and untested asymptomatic users (n=2,221,088, called “standard users” by the authors). Overall smoking prevalence was less in those tested (8.9%) than in all users of the app (11.0%). This might be thought of as a surprising finding – smoking-related symptoms should lead to testing – but can probably be explained by most asymptom...
The paper by Hopkinson et al (1) provides unique and important data on smoking prevalence and COVID-19 symptoms, but their conclusion does not reflect the data well. The authors conclude “these data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19”. The study includes over 150,000 people with self-reported COVID-19 symptoms and over two million without such symptoms. It also includes data on over 25,000 people who were tested for SARS-CoV-2 and their test results. Based on our analysis of these more relevant data, we interpret the study differently. Our conclusion would be “these data are consistent with smokers having an increased risk of symptoms such as cough and breathlessness, but a decreased risk of having SARS-CoV-2 infection”.
The difficulty in interpreting these results is that both symptoms and testing are likely colliders in a causal model of smoking and COVID-19. The data reported on SARS-CoV-2 test results make it possible to compare smoking prevalence by age-group and sex in three groups: those who tested positive for SARS-CoV-2 (n=7,123); those who tested negative (n=16,765); and untested asymptomatic users (n=2,221,088, called “standard users” by the authors). Overall smoking prevalence was less in those tested (8.9%) than in all users of the app (11.0%). This might be thought of as a surprising finding – smoking-related symptoms should lead to testing – but can probably be explained by most asymptomatic testing being in healthcare workers among whom smoking is less common. Importantly, smoking prevalence was appreciably lower in those who tested positive for SARS-CoV-2 (7.4%) than in both those who tested negative (9.3%) and in untested users (10.8%). The lower prevalence of smokers in app-users who tested positive was observed in all but one age-sex strata. In Table 1 https://shorturl.at/ovDL1 we reproduce the stratum-specific prevalence and provide two sets of odds ratios: one relative to participants who tested negative; and the other relative to standard users. If smoking causes similar symptoms to COVID-19 (e.g. persistent cough and shortness of breath) then using symptoms as a “test” for COVID-19 will more often lead to a false-positive in smokers than in non-smokers. This would explain the finding that the authors focus on, but it also means that one might expect lower prevalence of smoking in true-positives (i.e. those who test positive for SARS-CoV-2) than in false-positives (i.e. those who test negative). However, a different explanation is needed to explain the lower prevalence in test positive than in untested asymptomatic users. That might be because current smokers are at lower risk of SARS-CoV-2 infection, or it might be because asymptomatic smokers were less likely to be tested than asymptomatic non-smokers.
We note that the numbers of prevalent smokers in the authors’ Table 1 do not correspond to the percentages. This presumably is due to some users not completing the question regarding smoking. It is interesting to note that there were more people tested than those with either a positive or negative result. If, by subtraction, one calculates the prevalence of smoking among those tested who do not have a result, one finds that the prevalence of smoking is significantly (P<0.05) greater than amongst both those with a negative result (risk ratio 1.14) and those with a positive result (risk ratio 1.45).
These data are consistent with the unexpected observation made across a considerable number of studies that smokers have a decreased risk of COVID-19 (2). As with these previous observations, the results of this study could be an artefact of reporting and selection biases, but they certainly do not disprove the ‘protection’ hypothesis. The authors state that they have data to differentiate ex-smokers from current smokers, but unfortunately do not present them. Others have reported higher risk of COVID-19 in ex-smokers than in never smokers but also higher than in current smokers (2). As ex-smokers can be expected to lose the hypothetical protective effect of smoking but retain the health impact of their previous smoking, this makes the hypothesis more plausible. The fact that studies using similar approaches have detected a much higher risk in smokers to develop laboratory-confirmed influenza than non-smokers (3) also suggest that the finding of lower incidence of COVID-19 in smokers may not be just a methodological artefact. Several tentative hypotheses were proposed to explain the possible protective effect of smoking, including effects of nicotine on ACE receptors (4), effects on immune system of tobacco mosaic virus that typically colonizes airways of smokers (5), and thermic effects of regular inhalation of hot smoke on virus replication (2, 6).
There is no doubt that the harms of smoking hugely outweigh any benefits and that efforts to help smokers quit are important even in the time of pandemic. However, if current smoking causes a lowering of risk, then it is imperative to understand the mechanisms, because a better understanding could lead to new ways to reduce the risk of infection in the general population. Better data are urgently needed to clarify this potentially very important issue.
References:
1. Hopkinson NS, Rossi N, El-Sayed_Moustafa J, et al. Thorax Epub ahead of print. doi:10.1136/thoraxjnl-2020-216422
2. David Simons, Lion Shahab, Jamie Brown, Olga Perski. (2020). The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review with Bayesian meta-analyses (version 9). Qeios. doi:10.32388/UJR2AW.10.
3. Lawrence H, Hunter A, Murray R, Lim WS, McKeever T. Cigarette smoking and the occurrence of influenza - Systematic review. J Infect. 2019 Nov;79(5):401-406. doi: 10.1016/j.jinf.2019.08.014. Epub 2019 Aug 26. PMID: 31465780.
4. Farsalinos K, Angelopoulou A, Alexandris N, et al. COVID-19 and the nicotinic cholinergic system. Eur Respir J 2020 56: 2001589; DOI: 10.1183/13993003.01589-2020
5. de Bernardis E, Busà L. A putative role for the tobacco mosaic virus in smokers' resistance to COVID-19. Med Hypotheses. 2020;143:110153. doi:10.1016/j.mehy.2020.110153
6. Conti C, de Marco A, Mastromarino P, Tomao P, Santoro MG. Antiviral Effect of Hyperthermic Treatment in Rhinovirus Infection. Antimicrob Agents Chemother 1999; 43: 822–9.
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.
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.
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
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.
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.
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
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.
With great interest we have read the study by Deshayes et al. The authors present two cases of silvernitrate (AgNO3) aspiration in laryngectomized patients.
Show More1) In both cases the applicator tip broke off.
2) The authors conclude that treatment should comprise oral antibiotics and one should refrain from bronchial washing with sodium chloride solution.
With this response we would like to reply to both points addressed above.
1.
Five years ago we were confronted with the aspiration of an AgNO3 applicator tip in a laryngectomized patient. After the incident we analyzed the case to prevent future AgNO3 applicator tip aspiration. The AgNO3 pencil, used in both our case and the cases in the current article, is specifically designed to treat dermal lesions like verruca which requires repeated use. The pencil therefore contains a relatively large volume of AgNO3. AgNO3 is a brittle substance. When the pencil is used with a little too much pressure there is risk for the tip to break, and when used in a tracheostomy, there is risk for aspiration.
Our case led us to immediately stop using the AgNO3 pencils for treatment of granulation tissue in a tracheostomy. We strongly recommend the use of disposable AgNO3 cutaneous sticks for the treatment of granulation tissue around a tracheostomy. The disposable sticks contains less volume of AgNO3. Moreover, the stick is easier to use in narrow spaces like a tracheostomy.
2.
Aspiration of AgNO3 i...
We read with interest the recent study by our colleagues Tan et al (1) which reported the introduction of public health measures during the pandemic, such as social distancing and universal mask wearing, were observed to coincide with a marked reduction in transmission of other circulating respiratory viral infections. They reported a reduction in hospital admissions with acute exacerbation of COPD (AECOPD) by over 50% during the six month period of the pandemic from February to June 2020. They supported this observation with microbiological data showing a significant reduction in PCR-positive respiratory viral infections compared to the pre-pandemic era.
Ireland has the highest rate of hospitalisations for AECOPD in all OECD Countries (2). The first case of COVID-19 in the Republic of Ireland was reported on 29/02/2020 and stringent public health measures were introduced in mid-March to combat the spread (3).
We wish to describe our experiences of hospital admission with AECOPD during the first wave of the pandemic in a tertiary referral hospital in the West of Ireland. In our clinical practice, we noticed a reduction in patients admitted with COPD exacerbations at the beginning of the pandemic. We aimed to evaluate the impact of these infection control measures on our COPD population.
We conducted a retrospective cohort study of electronic health care records of patients who were hospitalised with a primary diagnosis of AECOPD over the four-month per...
Show MoreThe paper by Hopkinson et al (1) provides unique and important data on smoking prevalence and COVID-19 symptoms, but their conclusion does not reflect the data well. The authors conclude “these data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19”. The study includes over 150,000 people with self-reported COVID-19 symptoms and over two million without such symptoms. It also includes data on over 25,000 people who were tested for SARS-CoV-2 and their test results. Based on our analysis of these more relevant data, we interpret the study differently. Our conclusion would be “these data are consistent with smokers having an increased risk of symptoms such as cough and breathlessness, but a decreased risk of having SARS-CoV-2 infection”.
The difficulty in interpreting these results is that both symptoms and testing are likely colliders in a causal model of smoking and COVID-19. The data reported on SARS-CoV-2 test results make it possible to compare smoking prevalence by age-group and sex in three groups: those who tested positive for SARS-CoV-2 (n=7,123); those who tested negative (n=16,765); and untested asymptomatic users (n=2,221,088, called “standard users” by the authors). Overall smoking prevalence was less in those tested (8.9%) than in all users of the app (11.0%). This might be thought of as a surprising finding – smoking-related symptoms should lead to testing – but can probably be explained by most asymptom...
Show MoreVitamin 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...
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...
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...
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...
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.
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...
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.
Pages