We thank Tanimura and colleagues for their thoughtful commentary on our recent manuscript, “Respiratory exacerbations are associated with muscle loss in current and former smokers” and read their analysis of erector spinae muscle area (ESMA) with interest (1). In their commentary, they note that muscle loss can occur heterogeneously, with the greatest expected impact on the muscles of ambulation. They suggest that erector spinae muscles, due to their fiber composition and anti-gravity role, are a better reflection of inactivity-related muscle loss and posit that changes in pectoralis muscle area (PMA) may only reflect changes in nutrition (as measured by body mass index, BMI).
We agree that muscle loss is unlikely to be uniform; however, a disconnect has been reported between the postural muscles of the trunk and ambulatory muscle (e.g. quadriceps) weakness, despite similar fiber types (2). Few studies measure both groups of muscles simultaneously, but there is evidence that inspiratory force is more affected than peripheral muscle force in patients with COPD; implying that deconditioning is not the sole driver of muscle dysfunction (3). While the pectoralis muscle potentially underestimates inactivity-related atrophy, these studies suggest its role as an accessory muscle of inspiration makes it a reasonable target for capturing any underlying systemic process.
In contrast to Tanimura et al’s findings, in the COPDGene participants (n=8,603) BMI was more stro...
We thank Tanimura and colleagues for their thoughtful commentary on our recent manuscript, “Respiratory exacerbations are associated with muscle loss in current and former smokers” and read their analysis of erector spinae muscle area (ESMA) with interest (1). In their commentary, they note that muscle loss can occur heterogeneously, with the greatest expected impact on the muscles of ambulation. They suggest that erector spinae muscles, due to their fiber composition and anti-gravity role, are a better reflection of inactivity-related muscle loss and posit that changes in pectoralis muscle area (PMA) may only reflect changes in nutrition (as measured by body mass index, BMI).
We agree that muscle loss is unlikely to be uniform; however, a disconnect has been reported between the postural muscles of the trunk and ambulatory muscle (e.g. quadriceps) weakness, despite similar fiber types (2). Few studies measure both groups of muscles simultaneously, but there is evidence that inspiratory force is more affected than peripheral muscle force in patients with COPD; implying that deconditioning is not the sole driver of muscle dysfunction (3). While the pectoralis muscle potentially underestimates inactivity-related atrophy, these studies suggest its role as an accessory muscle of inspiration makes it a reasonable target for capturing any underlying systemic process.
In contrast to Tanimura et al’s findings, in the COPDGene participants (n=8,603) BMI was more strongly correlated with ESMA (r=0.42, p<0.001) than PMA (r=0.17, p< 0.001). Interestingly, both correlations were stronger in women compared to men. Because change in pectoral muscle area (PMA) is mildly correlated with change in BMI (r=0.20, p>0.001), our longitudinal analysis included BMI as a predictor.
Building on previously published work showing no association between ESMA and mortality in COPDGene participants without obstruction (4), we completed a sex-stratified analysis of n=8,603 participants over 12 years of follow-up using a Cox proportional hazards model controlling for age, race, smoking status, pack years, dyspnea score (MMRC), six-minute walk distance, FEV1 percent predicted, percent emphysema, and BMI. We found that the ESMA was not significantly associated with mortality (p=0.125 for men and p=0.157 for women). In an analogous model, PMA was associated with mortality; for each one cm2 decrease in PMA, men had a 1.1% (0.5-1.8%, p<0.001) increased risk of death and women had a 1.6% (0.3-2.9%, p=0.016) increased risk of death.
Differences in the cohort composition, measurement interval, and statistical methods in our work and that of Tanimura et. al. could be contributing to the discrepant results in our studies. For example, compared to their cohort, the men in COPDGene were substantially younger (59.6 ± 9.0 years), had higher BMI (28.4 ± 5.5 kg/m2), and had nearly twice the mean PMA (51.2 ± 15.6 cm2) and ESMA (58.7 ± 12.2 cm2). Additionally, we note that in COPDGene women had significantly lower ESMA (43.1 ± 9.4 cm2) and PMA (31.2 ± 8.3 cm2) and Black/African American participants had significantly higher ESMA (57.1 ± 13.9 cm2 vs 48.7 ± 12.5 cm2) and PMA (51.4 ± 18.4 cm2 vs 37.6 ± 12.9 cm2) compared to non-Hispanic Whites. The former finding is especially notable in the context of literature demonstrating differential muscle dysfunction in men and women with COPD (5, 6).
In conclusion, our analysis demonstrated that PMA is not only associated with exacerbations, but with mortality. We found significant differences in ESMA and PMA measurements across sex and race categories that may impact the generalizability of studies using cross-sectional muscle area as a proxy for fat free mass. Further research with broad, inclusive cohorts may help elucidate anthropometric differences in disease progression.
1. Mason SE, Moreta-Martinez R, Labaki WW, Strand M, Baraghoshi D, Regan EA, et al. Respiratory exacerbations are associated with muscle loss in current and former smokers. Thorax. 2021.
2. Man WD, Hopkinson NS, Harraf F, Nikoletou D, Polkey MI, Moxham J. Abdominal muscle and quadriceps strength in chronic obstructive pulmonary disease. Thorax. 2005;60(9):718-22.
3. Gosselink R, Troosters T, Decramer M. Distribution of muscle weakness in patients with stable chronic obstructive pulmonary disease. J Cardiopulm Rehabil. 2000;20(6):353-60.
4. Diaz AA, Martinez CH, Harmouche R, Young TP, McDonald ML, Ross JC, et al. Pectoralis muscle area and mortality in smokers without airflow obstruction. Respir Res. 2018;19(1):62.
5. Sharanya A, Ciano M, Withana S, Kemp PR, Polkey MI, Sathyapala SA. Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities. Chron Respir Dis. 2019;16:1479973119843650.
6. Ausin P, Martinez-Llorens J, Sabate-Bresco M, Casadevall C, Barreiro E, Gea J. Sex differences in function and structure of the quadriceps muscle in chronic obstructive pulmonary disease patients. Chron Respir Dis. 2017;14(2):127-39.
We thank Brennan et al, for sharing their experiences. In contrast to our observed reduction of more than 50% in AECOPD hospital admissions over a 6-month period, Brennan and colleagues observed a reduction of only 18% over a 4-month period. In addition, while we saw a significant and sustained decrease, Brennan et al. observed a decrease only in the first month following lockdown. At the fundamental level, respiratory viruses can spread either via contact, droplet or aerosols[1] and thus in theory mask wearing, social distancing and increased personal respiratory etiquette and community hygiene would reduce transmission and contribute to reduced incidence of AECOPD. The use of masks has been shown to reduce exposure to acute respiratory viruses by 46%[2].
We hypothesise that these differences could potentially be due to variations in the degree of adherence to mask wearing/social distancing, as well as nuances in public health measures introduced in various countries during the COVID-19 pandemic.
For instance, Singapore had mandated face-mask wearing in April 2020. The observations reported by Brennan et al terminated in June 2020 while Ireland only mandated face-mask wearing in August 2020. and hence may not have captured the impact of compulsory mask wearing. The difference in timing of implementation and enforcement of government policies during the COVID-19 pandemic possibly contributed to a different experience in Ireland.
We thank Brennan et al, for sharing their experiences. In contrast to our observed reduction of more than 50% in AECOPD hospital admissions over a 6-month period, Brennan and colleagues observed a reduction of only 18% over a 4-month period. In addition, while we saw a significant and sustained decrease, Brennan et al. observed a decrease only in the first month following lockdown. At the fundamental level, respiratory viruses can spread either via contact, droplet or aerosols[1] and thus in theory mask wearing, social distancing and increased personal respiratory etiquette and community hygiene would reduce transmission and contribute to reduced incidence of AECOPD. The use of masks has been shown to reduce exposure to acute respiratory viruses by 46%[2].
We hypothesise that these differences could potentially be due to variations in the degree of adherence to mask wearing/social distancing, as well as nuances in public health measures introduced in various countries during the COVID-19 pandemic.
For instance, Singapore had mandated face-mask wearing in April 2020. The observations reported by Brennan et al terminated in June 2020 while Ireland only mandated face-mask wearing in August 2020. and hence may not have captured the impact of compulsory mask wearing. The difference in timing of implementation and enforcement of government policies during the COVID-19 pandemic possibly contributed to a different experience in Ireland.
Aside from early implementation and mandatory public health measures, efforts from the government are also needed to maximise adoption of these public health measures. Egan et al conducted a study to evaluate the effect of infographics on public recall, sentiment and willingness to use face-masks during COVID-19[3]. The study showed that recall of the salient steps of effective mask wearing was significantly higher in participants who viewed the Singaporean Ministry of Health infographic. In addition, acknowledging the impact of pandemic public health measures on personal lives of the public, health messaging in Singapore has encouraged and emphasised social responsibility. These came in the form of financial aids to businesses and citizens and also fines for failure to comply to health policies[4]. Thus, while various countries may be implementing the same public health measures, enforcement and adherence by the public may differ. Further efforts by the government are essential to maximise adoption and these can vary between countries due to differences in political systems[5].
In Singapore, a recent survey showed that as of January 3 2021, 91% of Singaporean respondents stated compliance to face mask wearing in public places during the COVID-19 outbreak, up from 24% on Feb 21, 2020. In fact, by end April 2020, compliance rate was already 90%[6]. In Hong Kong, the compliance of face mask usage by HKSAR general public was 96.6% (range: 95.7% to 97.2%)[7]. Comparatively, in a large community survey conducted in Ireland, when self-reported compliance with health guidance (including hand hygiene, social distancing, mask wearing and other public health measures) was assessed on an 11-point score, the average score was only 7.44 (S.D 2.48)[8].
In conclusion, the different experience by Brennan and colleagues are interesting yet not unexpected. Enforcement and adherence to public health measures during a pandemic will vary from country to country. These are affected by the country’s organizational system as well as at an individual level – the public’s attitudes and socioeconomic behaviour during a pandemic which translate to adherence to strict public health measures.
References
1. Kutter JS, Spronken MI, Fraaij PL, et al. Transmission routes of respiratory viruses among humans. Curr Opin Virol 2018;28:142-51. doi: 10.1016/j.coviro.2018.01.001 [published Online First: 2018/02/18]
2. Jefferson T, Del Mar CB, Dooley L, et al. Physical interventions to interrupt or reduce the spread of respiratory viruses. Cochrane Database of Systematic Reviews 2020(11) doi: 10.1002/14651858.CD006207.pub5
3. Egan M, Acharya A, Sounderajah V, et al. Evaluating the effect of infographics on public recall, sentiment and willingness to use face masks during the COVID-19 pandemic: a randomised internet-based questionnaire study. BMC Public Health 2021;21(1):367. doi: 10.1186/s12889-021-10356-0 [published Online First: 2021/02/19]
4. Chua AQ, Tan MMJ, Verma M, et al. Health system resilience in managing the COVID-19 pandemic: lessons from Singapore. BMJ Glob Health 2020;5(9) doi: 10.1136/bmjgh-2020-003317 [published Online First: 2020/09/18]
5. Abdullah WJ, Kim S. Singapore’s Responses to the COVID-19 Outbreak: A Critical Assessment. The American Review of Public Administration 2020;50(6-7):770-76. doi: 10.1177/0275074020942454
6. Hirschmann R. Share of people who wore masks in public COVID-19 pandemic in Singapore 2020-2021. January 2021. https://www.statista.com/statistics/1110983/singapore-wearing-masks-duri....
7. Cheng VC, Wong SC, Chuang VW, et al. The role of community-wide wearing of face mask for control of coronavirus disease 2019 (COVID-19) epidemic due to SARS-CoV-2. J Infect 2020;81(1):107-14. doi: 10.1016/j.jinf.2020.04.024 [published Online First: 2020/04/27]
8. Roozenbeek J, Schneider CR, Dryhurst S, et al. Susceptibility to misinformation about COVID-19 around the world. R Soc Open Sci 2020;7(10):201199. doi: 10.1098/rsos.201199 [published Online First: 2020/11/19]
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 influence of obesity on both asthma and T2 biomarkers remains poorly understood and we fully agree this requires further investigation, as does the relationship between obesity, depression and persistent symptoms of breathlessness. However, the data correlating obesity and FeNO is conflicting and the reported weak positive associations have often not been adjusted for corticosteroid dose and may simply reflect higher doses of corticosteroid therapy in more breathless obese patients than by those of normal weight, rather than a specific mechanistic relationship.
Moreover, the UKSAR population appears very different from the cohorts described in some of these reports. For example, the average FeNO was only 25ppb in the Komakula study, whilst in the study by Lugogo subjects were predominantly T2-low across all BMI categories: the upper quartile value of blood eosinophils in both lean and obese groups was <300 cells/µL, whilst the upper quartile of FeNO in both lean and obese groups was <30ppb. In contrast, even in the UKSAR T2 high cohort, the mean BMI was in the obese range.
The nature and veracity of the ‘T2-low’ phenotype remains unclear, particularly in severe asthma. What is increasingly apparent is that patients are frequently prescribed high dose inhaled and systemic corticosteroids for respiratory symptoms, which suppresses T2 inflammation in the process. In the context of obesity and other co-morbidities known to be associated with increased re...
The influence of obesity on both asthma and T2 biomarkers remains poorly understood and we fully agree this requires further investigation, as does the relationship between obesity, depression and persistent symptoms of breathlessness. However, the data correlating obesity and FeNO is conflicting and the reported weak positive associations have often not been adjusted for corticosteroid dose and may simply reflect higher doses of corticosteroid therapy in more breathless obese patients than by those of normal weight, rather than a specific mechanistic relationship.
Moreover, the UKSAR population appears very different from the cohorts described in some of these reports. For example, the average FeNO was only 25ppb in the Komakula study, whilst in the study by Lugogo subjects were predominantly T2-low across all BMI categories: the upper quartile value of blood eosinophils in both lean and obese groups was <300 cells/µL, whilst the upper quartile of FeNO in both lean and obese groups was <30ppb. In contrast, even in the UKSAR T2 high cohort, the mean BMI was in the obese range.
The nature and veracity of the ‘T2-low’ phenotype remains unclear, particularly in severe asthma. What is increasingly apparent is that patients are frequently prescribed high dose inhaled and systemic corticosteroids for respiratory symptoms, which suppresses T2 inflammation in the process. In the context of obesity and other co-morbidities known to be associated with increased respiratory symptoms, such as breathing pattern disorders and laryngeal dysfunction, this leads to high levels of avoidable corticosteroid-induced toxicity. The recent study by Heaney and colleagues in the RASP-UK programme, demonstrated that when corticosteroids were reduced based on T2-biomarkers, the maximal prevalence of T2-Low severe asthma was ~5%. Importantly in the sub-group analysis of patients with “uncontrolled asthma” defined as ACQ-7≥1.5, biomarker directed care resulted in significant reduction of corticosteroid treatment with no loss of control and patients in this uncontrolled group were predominantly female, obese with restrictive lung function, more likely to be on oral corticosteroids and with higher levels of reflux, depression and osteoporosis, all consistent with corticosteroid overtreatment.
Until such time as corticosteroid doses are more effectively optimized in a T2 biomarker directed fashion, the influence of steroids themselves on many inflammatory pathways will continue to hamper our understanding of what mechanistically constitutes ‘T2-low’ asthma.
References
Komakula S, Khatri S, Mermis J, et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir Res. 2007Apr 16;8(1):32.
Lugogo N, Green CL, Agada N, et al. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol. 2018;141(3):1096-1104.
Heaney LG, Busby J, Hanratty CE, et al. Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. 2021 Jan;9(1):57-68.
We read with interest the recent paper from DJ Jackson et al, “Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era” [1], and share their concerns regarding the risk of excessive corticosteroid exposure in T2-low individuals. We congratulate the authors for gathering such an extensive range of data in this large cohort of people with severe asthma, enabling meaningful comparisons, particularly between biologic and non-biologic populations. We echo the call for further work to identify and validate pragmatic T2-low endotype-specific biomarkers through clearer understanding of this inflammatory cascade. This cohort of patients continues to be under-served, made all the more evident by the paucity of novel therapies in this era of precision medicine.
We note the authors’ comments on T2-biomarker increase with corticosteroid dose reduction, and the presence of a historic T2-high profile in some individuals from the T2-low group. Whilst the postulated explanation reported by the authors, one of corticosteroid-induced T2-biomarker suppression, is undoubtedly a key factor (and indeed supported by the significant difference in corticosteroids between the groups), we would suggest another important factor that may be relevant to the understanding of the T2-low pathway.
The authors report a significant difference in BMI between T2-high and T2-low groups (30.2kg/m2 and 32.1kg/m2 respectively, P-value = <0.001). Whilst the...
We read with interest the recent paper from DJ Jackson et al, “Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era” [1], and share their concerns regarding the risk of excessive corticosteroid exposure in T2-low individuals. We congratulate the authors for gathering such an extensive range of data in this large cohort of people with severe asthma, enabling meaningful comparisons, particularly between biologic and non-biologic populations. We echo the call for further work to identify and validate pragmatic T2-low endotype-specific biomarkers through clearer understanding of this inflammatory cascade. This cohort of patients continues to be under-served, made all the more evident by the paucity of novel therapies in this era of precision medicine.
We note the authors’ comments on T2-biomarker increase with corticosteroid dose reduction, and the presence of a historic T2-high profile in some individuals from the T2-low group. Whilst the postulated explanation reported by the authors, one of corticosteroid-induced T2-biomarker suppression, is undoubtedly a key factor (and indeed supported by the significant difference in corticosteroids between the groups), we would suggest another important factor that may be relevant to the understanding of the T2-low pathway.
The authors report a significant difference in BMI between T2-high and T2-low groups (30.2kg/m2 and 32.1kg/m2 respectively, P-value = <0.001). Whilst the absolute difference may seem trivial, raised BMI directly affects levels of commonly used T2-biomarkers [2,3,4]. With regards to fractional exhaled nitric oxide (FeNO), there is evidence for an adipose-mediated metabolic imbalance with nitric oxide synthase (NOS) uncoupling that affects NO bioavailability and leads to reduced FeNO [5]. In obesity-associated asthma, whilst total IgE and blood eosinophils correlate to T2-high profiles, this association is relatively weaker and total IgE levels are lower compared to healthy-BMI people with asthma. Furthermore, neither IgE, blood eosinophils nor FeNO predict sputum eosinophilia with current ranges, and evidence suggests lower thresholds are needed for T2-biomarkers in this cohort [4]. This has important implications for asthma phenotyping, monitoring of response to treatment and, as is a focus of the article, determining eligibility for advanced therapies. We would also suggest the difference in depression and anxiety seen within the two groups may be somewhat related to the BMI disparity.
Obesity-associated asthma remains incompletely understood, however it is becoming clearer that focus is needed on identifying biomarkers and specific treatments for severe T2 low asthma and this may be particularly relevant to the this population.
References
[1] – Jackson DJ, Busby J, Pfeffer PE, et al; UK Severe Asthma Registry. Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era. Thorax. 2021Mar;76(3):220-227.
[2] – Komakula S, Khatri S, Mermis J, et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir Res. 2007Apr 16;8(1):32.
[3] – Renata Barros, André Moreira, João Fonseca, et al. Obesity and airway inflammation in asthma. Journal of Allergy and Clinical Immunology. 2006;117:6(1501-1502), ISSN 0091-6749,
[4] – Lugogo N, Green CL, Agada N, et al. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol. 2018;141(3):1096-1104.
[5] – Holguin F, Grasemann H, Sharma S, et al. L-Citrulline increases nitric oxide and improves control in obese asthmatics. JCI Insight. 2019 Dec 19;4(24):e131733.
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.
We thank Tanimura and colleagues for their thoughtful commentary on our recent manuscript, “Respiratory exacerbations are associated with muscle loss in current and former smokers” and read their analysis of erector spinae muscle area (ESMA) with interest (1). In their commentary, they note that muscle loss can occur heterogeneously, with the greatest expected impact on the muscles of ambulation. They suggest that erector spinae muscles, due to their fiber composition and anti-gravity role, are a better reflection of inactivity-related muscle loss and posit that changes in pectoralis muscle area (PMA) may only reflect changes in nutrition (as measured by body mass index, BMI).
We agree that muscle loss is unlikely to be uniform; however, a disconnect has been reported between the postural muscles of the trunk and ambulatory muscle (e.g. quadriceps) weakness, despite similar fiber types (2). Few studies measure both groups of muscles simultaneously, but there is evidence that inspiratory force is more affected than peripheral muscle force in patients with COPD; implying that deconditioning is not the sole driver of muscle dysfunction (3). While the pectoralis muscle potentially underestimates inactivity-related atrophy, these studies suggest its role as an accessory muscle of inspiration makes it a reasonable target for capturing any underlying systemic process.
In contrast to Tanimura et al’s findings, in the COPDGene participants (n=8,603) BMI was more stro...
Show MoreWe thank Brennan et al, for sharing their experiences. In contrast to our observed reduction of more than 50% in AECOPD hospital admissions over a 6-month period, Brennan and colleagues observed a reduction of only 18% over a 4-month period. In addition, while we saw a significant and sustained decrease, Brennan et al. observed a decrease only in the first month following lockdown. At the fundamental level, respiratory viruses can spread either via contact, droplet or aerosols[1] and thus in theory mask wearing, social distancing and increased personal respiratory etiquette and community hygiene would reduce transmission and contribute to reduced incidence of AECOPD. The use of masks has been shown to reduce exposure to acute respiratory viruses by 46%[2].
We hypothesise that these differences could potentially be due to variations in the degree of adherence to mask wearing/social distancing, as well as nuances in public health measures introduced in various countries during the COVID-19 pandemic.
For instance, Singapore had mandated face-mask wearing in April 2020. The observations reported by Brennan et al terminated in June 2020 while Ireland only mandated face-mask wearing in August 2020. and hence may not have captured the impact of compulsory mask wearing. The difference in timing of implementation and enforcement of government policies during the COVID-19 pandemic possibly contributed to a different experience in Ireland.
Aside from early impleme...
Show MoreWe 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 influence of obesity on both asthma and T2 biomarkers remains poorly understood and we fully agree this requires further investigation, as does the relationship between obesity, depression and persistent symptoms of breathlessness. However, the data correlating obesity and FeNO is conflicting and the reported weak positive associations have often not been adjusted for corticosteroid dose and may simply reflect higher doses of corticosteroid therapy in more breathless obese patients than by those of normal weight, rather than a specific mechanistic relationship.
Show MoreMoreover, the UKSAR population appears very different from the cohorts described in some of these reports. For example, the average FeNO was only 25ppb in the Komakula study, whilst in the study by Lugogo subjects were predominantly T2-low across all BMI categories: the upper quartile value of blood eosinophils in both lean and obese groups was <300 cells/µL, whilst the upper quartile of FeNO in both lean and obese groups was <30ppb. In contrast, even in the UKSAR T2 high cohort, the mean BMI was in the obese range.
The nature and veracity of the ‘T2-low’ phenotype remains unclear, particularly in severe asthma. What is increasingly apparent is that patients are frequently prescribed high dose inhaled and systemic corticosteroids for respiratory symptoms, which suppresses T2 inflammation in the process. In the context of obesity and other co-morbidities known to be associated with increased re...
We read with interest the recent paper from DJ Jackson et al, “Characterisation of patients with severe asthma in the UK Severe Asthma Registry in the biologic era” [1], and share their concerns regarding the risk of excessive corticosteroid exposure in T2-low individuals. We congratulate the authors for gathering such an extensive range of data in this large cohort of people with severe asthma, enabling meaningful comparisons, particularly between biologic and non-biologic populations. We echo the call for further work to identify and validate pragmatic T2-low endotype-specific biomarkers through clearer understanding of this inflammatory cascade. This cohort of patients continues to be under-served, made all the more evident by the paucity of novel therapies in this era of precision medicine.
Show MoreWe note the authors’ comments on T2-biomarker increase with corticosteroid dose reduction, and the presence of a historic T2-high profile in some individuals from the T2-low group. Whilst the postulated explanation reported by the authors, one of corticosteroid-induced T2-biomarker suppression, is undoubtedly a key factor (and indeed supported by the significant difference in corticosteroids between the groups), we would suggest another important factor that may be relevant to the understanding of the T2-low pathway.
The authors report a significant difference in BMI between T2-high and T2-low groups (30.2kg/m2 and 32.1kg/m2 respectively, P-value = <0.001). Whilst the...
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.
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