Thank you to the authors for this important and detailed analysis. I write to simply draw attention to a discrepancy, unless I am mistaken, between the ATE frequency rates stated in the abstract and those in the main text.
Abstract: "The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively".
Main text: "The weighted frequency of ATE was 4.0% (95%CI 2.0% to 6.5%, I2 =95%; 19 studies; 8249 patients), including myocardial
infarction/acute coronary syndrome (1.1%, 95%CI 0.2% to 3.0%, I2=96%; 16 studies; 7939 patients), ischaemic stroke (1.6%, 95%CI 1.0% to 2.2%, I2 =93%; 27 studies; 40597 patients) and other ATE (0.9%, 95%CI 0.5% to 1.5%; I2
=84%; 17 studies; 20139 patients)
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of LVR during exacerbations and in individuals with lower pulmonary function, the optimal timing for routine LVR therapy was not identified in our study of younger individuals with preserved lung function. While it would be ideal to conduct a randomized trial of LVR therapy in individuals with DMD beginning at the apex of their vital capacity trajectory,[9] a lengthy and costly study would be needed to evaluate changes over several years in order to determine the benefits of LVR. In contrast, such a study is not needed in individuals with advanced disease, in whom there is sufficient evidence to justify regular treatment. Given that uptake of routine LVR therapy for individuals with neuromuscular disease is not uniform, additional evidence is still needed to guide best practices for clinical care. Further exploration is required to ensure that LVR is introduced when it will be of benefit to individuals with neuromuscular disease.
References
1. Birnkrant DJ, Bushby KM, Amin RS, et al. The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatric Pulmonology 2010;45(8):739-48.
2. Amin RM, I; Zielinski,D; Adderley,R; Carnevale,F; Chiang,J; Cote,A; Daniels,C; Daigneault,P; Harrison.C; Katz,S; Keilty,K; Majaesic,C; Moraes.T.J; Price,A; Radhakrishnan,D; Rapoport,A; Spier,S; Thavagnanam,S; Witmans,M; Canadian Thoracic Society. Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary. Canadian Journal of Respiratory, Critical Care and Sleep Medicine 2017;1(1):7-36.
3. Hull J, Aniapravan R, Chan E, et al. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax 2012;67 Suppl 1:i1-40.
4. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170(4):456-65.
5. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018;17(4):347-61. doi: 10.1016/s1474-4422(18)30025-5 [published Online First: 2018/02/06]
6. Birnkrant DJ. The American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Pediatrics 2009;123 Suppl 4:S242-S44.
7. McKim DA, Katz SL, Barrowman N, et al. Lung Volume Recruitment Slows Pulmonary Function Decline in Duchenne Muscular Dystrophy. Archives of Physical Medicine and Rehabilitation 2012;93(7):1117-22.
8. Katz SL, Barrowman N, Monsour A, et al. Long-Term Effects of Lung Volume Recruitment on Maximal Inspiratory Capacity and Vital Capacity in Duchenne Muscular Dystrophy. Ann Am Thorac Soc 2016;13(2):217-22.
9. Chiou M, Bach JR, Jethani L, et al. Active lung volume recruitment to preserve vital capacity in Duchenne muscular dystrophy. J Rehabil Med 2017;49(1):49-53. doi: 10.2340/16501977-2144 [published Online First: 2016/09/16]
10. McDonald CM, Gordish-Dressman H, Henricson EK, et al. Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids. Neuromuscul Disord 2018;28(11):897-909. doi: 10.1016/j.nmd.2018.07.004 [published Online First: 2018/10/20]
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached and begins to decrease. For patients with DMD, this decline occurs around 13.5 (range-9-17) years of age.6 At this point, cough flows tend to drastically decrease, increasing the risk of pneumonia, but can be improved with air stacking.2,3 Therefore, it is our opinion that air stacking is not a burden but when to initiate is arguable.
References
1. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):222-227.
2. Bach JR, Kang SW. Disorders of ventilation: weakness, stiffness, and mobilization. Chest 2000; 117(2):301-303.
3. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):
4. Rideau Y, Bach J. Efficacité therapeutique dans la dystrophie musculaire de Duchenne. J Readapt Med 1982;2(3):96-100.
5. Deo P, Bach JR. Noninvasive ventilatory support to reverse weight loss in Duchenne muscular dystrophy: a case series. Pulmonol 2019;25(2):79-82.
6. Bach J, Alba A, Lee M, Rideau Y. Long-term respiratory rehabilitation in the treatment of neuromuscular disease. Ann Readapt Med Phys 1983;26:101-109.
The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of...
The state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Observations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of exuded plasma (14). Intriguingly, as demonstrated with Coronavirus229E and rhinoviruses (3,4,6,13), the plasma exudation response lasts until resolution.
Epithelial barrier asymmetry: exuded plasma operates on an intact airway mucosa.
Subepithelial extravasation of plasma is controlled by active, fully reversible formation of gaps between postcapillary, venular endothelial cells. The subsequent epithelial transmission of plasma reflects a direction-specific elasticity of cell junctions in pseudostratified epithelium. Thus, when approached from beneath by minimally increased basolateral hydrostatic pressure, plasma macromolecules pass outwardly by epithelial mechanisms not available to molecules deposited on the mucosal surface (2). Most important, plasma exudation proceeds without affecting the normal barrier function of the epithelial lining. In accord, inflammatory airways diseases exhibit plasma exudation without sign of increased penetration of molecules deposited on the airway mucosal surface (9,13,14). The conspicuous asymmetry of the pseudostratified epithelium of human airways makes the plasma exudation response, with its omnipotent content, a first line innate respiratory defense response (15).
Plasma exudation building barrier and biological milieu at sites of epithelial regeneration.
To the extent that Covid-19 causes airways epithelial injury and shedding (1), plasma exudation would again be vitally involved (13,15-17). As in asthma, infection-induced loss of pseudostratified epithelium apparently emerges as a patchy, non-sanguineous event without damage to the basement membrane. In experimental in vivo studies, such asthma-like denudation, almost independent of cause, promptly induces local plasma exudation that covers the naked membrane with a fibrin/fibronectin gel. Further, this provisional barrier-gel is continuously supplied by exuded plasma proteins creating a biological milieu suited for prompt start and speedy progress of repair. In vivo, all types of epithelial cells bordering a denuded patch dedifferentiate into fast-migrating regeneration cells. As soon as a cellular barrier is established exudation stops and the gel is shed (15-17). At vulnerable airway denudation patches, local plasma exudation would contribute both a barrier and a biologically active milieu promoting antimicrobial defense and epithelial regeneration.
Summarizing: The above humoral aspect of mucosal defense in human airways with intact or regenerating epithelial lining is overlooked in currently leading notions (1). As listed elsewhere (2), numerous factors may contribute to this oversight. A major factor is unappreciation of the asymmetry of human airways epithelial barriers (15). Another concerns specificity. However, precision of airways plasma exudation resides not in molecular specificity but in its highly localized distribution along with strict control of its duration (2). A further shortcoming of the present complementary concepts concerns the fact that they are underpinned by classical observational medical research, which was outdated already in 1990s (18). Word count 595
References
1. Bridges JP, Vladar EK, Huang H, Mason RJ. Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19. Thorax 2022;77:203-209.
2. Persson C. Early humoral defense under the radar: microvascular-epithelial cooperation at airways infection in asthma and health. Am J Physiol Lung Cell Mol Physiol 2022;322:L503-L506. Doi:10.1152ajplung.00470.2021.
3. Proud D, Naclerio RM, Gwaltney JM, Hendley JO. Kinins are generated in nasal secretions during natural rhinovirus colds. J Infect Dis. 1990;161:120-123.
4. Åkerlund A, Greiff L, Andersson M, Bende M, Alkner U, Persson C. Mucosal exudation of fibrinogen in coronavirus-induced common colds. Acta Otolaryngol. 1993;113:642-648.
5. Pizzichini MMM, Pizzicini E, Efthimiadis A, et al. Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. Am J Respir Crit Care Med. 1998;158:1178-1184.
6. Winther B, Gwaltney JM Jr, Humphries JE, Hendley JO. Cross- linked fibrin in the nasal fluid of patients with common cold. Clin Infect Dis. 2002;34:708-710.
7. Stockley RA, Mistry M, Bradwell AR, Burnett D. A study of plasma proteins in the sol phase of sputum from patients with chronic bronchitis. Thorax. 1979;34:777-782
8. Van Vyve T, Chanez P, Bernard A, et al. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol. 1995;95:60-68.
9. Greiff L, Andersson M, Åkerlund A, et al. Microvascular exudative hyperresponsiveness in human coronavirus-induced common cold. Thorax. 1994;49:121-127.
10. Greiff L, Andersson M, Erjefalt JS, Svensson C, Persson CG. Loss of size- selectivity at histamine-induced exudation of plasma proteins in atopic nasal airways. Clin Physiol Funct Imaging. 2002;22:28-31.
11. Andersson M, Michel L, Llull JB, Pipkorn U. Complement activation on the nasal mucosal surface – a feature of the immediate allergic reaction in the nose. Allergy. 1994;49:242-245.
12. Svensson C, Baumgarten CR, Pipkorn U, Alkner U, Persson C. Reversibility and reproducibility of histamine-induced plasma leakage in nasal airways. Thorax. 1989;44:13-18.
13. Persson C. Humoral first-line mucosal innate defence in vivo. J Innate Immun. 2020;2020(12):373-386.
14. Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy. 2012;42:383-391.
15. Persson C. ‘Bedside’ observations challenge aspects of the ‘Epithelial barrier hypothesis’. Nat Rev Immunol 2021;21:829. https://doi.org/ 10.1038/s41577-021- 00650-8.
16. Persson CGA, Erjefält JS. Airway epithelial restitution following shedding and denudation. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The Lung: Scientific Foundations, 2nd edn. New York: Raven; 1997:2611-2627.
17. Persson C. Airways exudation of plasma macromolecules: innate defense, epithelial regeneration, and asthma. J Allergy Clin Immunol. 2019;143:1271–1286.
18. Persson C. Clinical research, or classical clinical research? Nat Med. 1999;5(7):714-715.
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilita...
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilitation programmes as a part of health services. Further information regarding costs, presentations to community services, and justification of the use of the CRQ-D tool would be valuable.
REFERENCES:
1. Bolton CE, Bevan-Smith EF, Blakey JD, et alBritish Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICEThorax 2013;68:ii1-ii30.
2. Wijkstra PJ, TenVergert EM, Van Altena R, Otten V, Postma DS, Kraan J, Koëter GH. Reliability and validity of the chronic respiratory questionnaire (CRQ). Thorax. 1994 May;49(5):465-7. doi: 10.1136/thx.49.5.465. PMID: 8016767; PMCID: PMC474867.
3. Singh SJ, Jones PW, Evans R, Morgan MD. Minimum clinically important improvement for the incremental shuttle walking test. Thorax. 2008 Sep;63(9):775-7. doi: 10.1136/thx.2007.081208. Epub 2008 Apr 4. PMID: 18390634.
4. Paul W Jones (2005) St. George's Respiratory Questionnaire: MCID, COPD: Journal of Chronic Obstructive Pulmonary Disease, 2:1, 75-79, DOI: 10.1081/COPD-200050513
We agree with Drs. Moolgavkar and Attanoos that our observation of increased risk of asbestosis unaccompanied by increased risk of mesothelioma among motor vehicle mechanics (Thomsen, 2021) is inconsistent with other studies of chrysotile exposed populations. As we discussed in our paper, mesothelioma ascertainment is highly reliable in Denmark and our mesothelioma findings are consistent with previous studies (DeBono, 2021; Garabrant, 2016; Hessel, 2021; Tomasallo, 2018; Van den Borre, 2015). Thus, we believe our findings are reliable. Conversely, the asbestosis findings raise important questions. A diagnosis of asbestosis can only be made when a clinician believes the patient has been exposed to asbestos. Pulmonary fibrosis in a vehicle mechanic might readily be diagnosed as asbestosis if the clinician was aware of the occupational history and possible presence of asbestos in brakes, clutches, gaskets, or other vehicle parts. Since our comparison subjects held jobs that did not involve obvious asbestos exposure, it is less likely that pulmonary fibrosis would be diagnosed as asbestosis in this group. Moolgavkar and Attanoos suggest that our comparison selection could have led to diagnostic bias if the vehicle mechanics and the comparisons did not have equal probabilities of exposure to asbestos from sources other than friction products. We agree - we reported that the abrupt increase in outpatient clinic diagnosed asbestosis beginning in the mid-2000s is consistent with...
We agree with Drs. Moolgavkar and Attanoos that our observation of increased risk of asbestosis unaccompanied by increased risk of mesothelioma among motor vehicle mechanics (Thomsen, 2021) is inconsistent with other studies of chrysotile exposed populations. As we discussed in our paper, mesothelioma ascertainment is highly reliable in Denmark and our mesothelioma findings are consistent with previous studies (DeBono, 2021; Garabrant, 2016; Hessel, 2021; Tomasallo, 2018; Van den Borre, 2015). Thus, we believe our findings are reliable. Conversely, the asbestosis findings raise important questions. A diagnosis of asbestosis can only be made when a clinician believes the patient has been exposed to asbestos. Pulmonary fibrosis in a vehicle mechanic might readily be diagnosed as asbestosis if the clinician was aware of the occupational history and possible presence of asbestos in brakes, clutches, gaskets, or other vehicle parts. Since our comparison subjects held jobs that did not involve obvious asbestos exposure, it is less likely that pulmonary fibrosis would be diagnosed as asbestosis in this group. Moolgavkar and Attanoos suggest that our comparison selection could have led to diagnostic bias if the vehicle mechanics and the comparisons did not have equal probabilities of exposure to asbestos from sources other than friction products. We agree - we reported that the abrupt increase in outpatient clinic diagnosed asbestosis beginning in the mid-2000s is consistent with diagnostic bias.
Moolgavkar and Attanoos suggest that we could clarify our results if we had complete occupational histories in the vehicle mechanic and comparison groups. Unfortunately, we do not have these histories, nor do we believe we could reliably estimate asbestos exposure in every historic job segment if we had them. They also suggest that we should give a clear description of how the definition of asbestosis has changed over the period of the study and how the level of exposure required for labeling interstitial fibrosis as asbestosis has evolved. We do not believe this is feasible because the diagnosis of asbestosis is not centralized to a few hospitals in Denmark and we are not aware of any resource that describes how the definition of asbestosis has changed over time. Their final suggestion, that we examine the risks of interstitial lung disease in the vehicle mechanics and the comparisons to see whether the risk of interstitial fibrosis other than asbestosis differs between the groups, is a good idea that might indicate whether one group was preferentially diagnosed with asbestosis. We will explore the feasibility of doing this.
References
1. DeBono NL, Warden H, Logar-Henderson C, Shakik S, Dakouo M, MacLeod J, et al. Incidence of mesothelioma and asbestosis by occupation in a diverse workforce. Am J Ind Med. 2021;64(6):476-87. Epub 2021/04/10.
2. Garabrant DH, Alexander DD, Miller PE, Fryzek JP, Boffetta P, Teta MJ, et al. Mesothelioma among Motor Vehicle Mechanics: An Updated Review and Meta-analysis. AnnOccupHyg. 2016;60(1):8-28.
3. Hessel PA. Mesothelioma among vehicle mechanics: a controversy? Thorax. 2021. Epub 20211105.
4. Thomsen RW, Riis AH, Flachs EM, Garabrant DH, Bonde JPE, Toft Sorensen H. Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. Thorax. 2021. Epub 2021/07/11.
5. Tomasallo CD, Christensen KY, Raymond M, Creswell PD, Anderson HA, Meiman JG. An Occupational Legacy: Malignant Mesothelioma Incidence and Mortality in Wisconsin. J Occup Environ Med. 2018;60(12):1143-9.
6. Van den Borre L, Deboosere P. Enduring health effects of asbestos use in Belgian industries: a record-linked cohort study of cause-specific mortality (2001-2009). BMJ Open. 2015;5(6):e007384-e.
Thomsen et al’s. (2021)1 suggestion that “asbestosis occurs at cumulative chrysotile exposure levels where mesotheliomas are rare or none were observed…”.to explain the increased risk of asbestosis in the absence of an increased risk of mesothelioma among vehicle mechanics appears implausible for many reasons:
a. Scientific literature shows that when there is a risk of asbestosis there is also an increased risk of pleural mesothelioma2;
b. Cumulative exposures to chrysotile asbestos sustained by career vehicle mechanics are far below the cumulative asbestos exposures traditionally associated with asbestosis (25 fibre/cc-years) as cited by Thomsen et al.1,3;
c. That chrysotile asbestos, with much shorter biopersistence than amphibole asbestos, is more fibrogenic is biologically implausible, and inconsistent with the studies that show that the degree of lung fibrosis/asbestosis correlates with retained amphibole asbestos content, not chrysotile 3,4.
d. Fibre counts amongst vehicle mechanics with mesothelioma have been found to be either within control reference limits or show increased commercial amphibole asbestos, unrelated to friction exposures 2.
e. Animal studies do not report asbestosis or mesothelioma following high-dose inhalation exposures to brake dust with and without added chrysotile 5.
We consider, as Thomsen et al 1 did, that the most plausible explanation is diagnostic bias based on control selection.
In Thomsen et al...
Thomsen et al’s. (2021)1 suggestion that “asbestosis occurs at cumulative chrysotile exposure levels where mesotheliomas are rare or none were observed…”.to explain the increased risk of asbestosis in the absence of an increased risk of mesothelioma among vehicle mechanics appears implausible for many reasons:
a. Scientific literature shows that when there is a risk of asbestosis there is also an increased risk of pleural mesothelioma2;
b. Cumulative exposures to chrysotile asbestos sustained by career vehicle mechanics are far below the cumulative asbestos exposures traditionally associated with asbestosis (25 fibre/cc-years) as cited by Thomsen et al.1,3;
c. That chrysotile asbestos, with much shorter biopersistence than amphibole asbestos, is more fibrogenic is biologically implausible, and inconsistent with the studies that show that the degree of lung fibrosis/asbestosis correlates with retained amphibole asbestos content, not chrysotile 3,4.
d. Fibre counts amongst vehicle mechanics with mesothelioma have been found to be either within control reference limits or show increased commercial amphibole asbestos, unrelated to friction exposures 2.
e. Animal studies do not report asbestosis or mesothelioma following high-dose inhalation exposures to brake dust with and without added chrysotile 5.
We consider, as Thomsen et al 1 did, that the most plausible explanation is diagnostic bias based on control selection.
In Thomsen et al 1, the selection of controls ‘with no occupational asbestos exposures’ essentially minimises the identification of any asbestosis cases in this group. Central to a diagnosis of asbestosis is an evaluation of appropriate exposure. Because vehicle mechanics are considered to be exposed to chrysotile asbestos from friction products, clinicians would be more inclined to assign a label of asbestosis than another cause for interstitial lung fibrosis, in a vehicle mechanic than in a subject with no known occupational asbestos.
The choice of control subjects from occupations known not to be exposed to asbestos raises another quite distinct issue. Ideally, both the study and control groups should have equal probabilities of exposure to asbestos from sources other than friction products. A control group selected to include only occupations known not to be exposed to asbestos is appropriate only if the vehicle mechanics in the study group were not exposed to asbestos in another occupation. Because vehicle mechanics have technical skills to allow their engagement in occupations with asbestos this is unlikely. The choice of control group in the Thomsen et al.1 study could lead to an upward bias in the estimates of the risks of asbestos-associated diseases among vehicle mechanics; this increased risk could not be attributed to asbestos exposure sustained during work as a vehicle mechanic. However, the bias, if any, in this study appears small because it confirms no increased mesothelioma risk in vehicle mechanics.
It would be ideal to have complete occupational histories in both the vehicle mechanic and control group; these occupational histories could then be controlled in statistical analyses. Such ideal data are rarely available so what may be done with the available data. Here are our suggestions:
1.The authors should give a clear description of how the definition of asbestosis has changed over the period of the study and, in particular, how the level of exposure required for labelling interstitial fibrosis as asbestosis has evolved over the period of the study.
2.Because the risks of ‘lung disease due to external agents’ is the same in the study and controls, it would be of interest to investigate the reported risks of interstitial fibroses other than asbestosis in the two groups. An increased reported risk in the control group would support the conclusion that diagnostic bias explains the increased reported risk of asbestosis among vehicle mechanics.
This paper raises two fundamental questions with respect to the diagnoses of pulmonary fibrosis and of asbestosis specifically. First, were cases of fibrosis preferentially diagnosed in either the study group or the controls? Second, was asbestosis preferentially diagnosed in one of the two groups? These questions could be addressed if appropriate clinical records were available for the study subjects. A random sample of these clinical records with occupational history expunged could be evaluated by a panel of experts blinded to the group allocation, whether vehicle mechanic or control, from which the records were sourced. This panel of experts could independently determine 1. whether or not the individual had interstitial fibrosis and 2. whether or not it could be diagnosed as asbestosis.
REFERENCES
1. Thomsen RW, Riis AH, Flachs EM, Garabrant DH, et al. Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. Thorax 2021 Jul 8; 10.1136/thoraxjnl-2020-215041.
2. Roggli VL, Sharma A: Analysis of tissue mineral fiber content, Ch. 11, In: Pathology of Asbestos Associated Diseases, 3rd Ed. (Oury TD, Sporn TA, Roggli VL eds.) Springer: New York, 2014, 253-292.
3. Roggli VL, Gibbs AR, Attanoos R, Churg A, Popper H, Cagle P, Corrin B, Franks T, Galateau-Sallé F, Galvin J, Hasleton P, Henderson D, Honma K: Pathology of Asbestosis: An Update of the Diagnostic Criteria. Report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society. Arch. Pathol. Lab. Med. 134: 462-480, 2010.
4. Green FH, Harley R, Vallyathan V, Althouse R, Fick G, Dement J, Mitha R, Pooley F. Exposure and mineralogical correlates of pulmonary fibrosis in chrysotile asbestos workers. Occup Environ Med. 1997 Aug;54(8):549-59.
5. Bernstein, D. M., B. Toth, R. A. Rogers, P. Kunzendorf, J. I. Phillips, and D. Schaudien. Final results from a 90-day quantitative inhalation toxicology study evaluating the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos: Histopathological examination, confocal microscopy and collagen quantification of the lung and pleural cavity. Toxicol Appl Pharmacol 2021; 424:115-598.
We thank A. Raja and colleagues for their interest in our article on risk factors for fibrotic-like changes after severe COVID-19 infection (1). We agree that identification and management of post-COVID fibrosis continues to be impeded by the lack of consensus definitions and we look forward to further studies that help describe the natural history of post-COVID pulmonary manifestations.
The authors propose that lung fibrosis be classified into different ILDs by the pattern of lung parenchymal abnormalities six months after the initial COVID illness has resolved. We agree with the authors that persistent radiographic abnormalities are an adverse outcome of COVID that deserve future study, but we disagree with their proposed classification of patterns. We believe that recognition of fibrotic interstitial lung abnormalities (ILAs), as opposed to non-fibrotic ILAs, help prognosticate which abnormalities are less likely to resolve over time (2). Han et al (3) recently demonstrated that individuals with post-COVID fibrotic ILAs at six months had persistent fibrosis at 1-year, suggesting that fibrotic ILAs rarely resolve completely. Ultimately, serial imaging, quantitative measures of fibrosis (4), and assessment of pharmaceutical interventions (5), will be key to fully understanding the trajectory of post-COVID fibrosis.
Secondly, the authors report that disease severity did not significantly impact the development of particular parenchymal abnormalities on CT...
We thank A. Raja and colleagues for their interest in our article on risk factors for fibrotic-like changes after severe COVID-19 infection (1). We agree that identification and management of post-COVID fibrosis continues to be impeded by the lack of consensus definitions and we look forward to further studies that help describe the natural history of post-COVID pulmonary manifestations.
The authors propose that lung fibrosis be classified into different ILDs by the pattern of lung parenchymal abnormalities six months after the initial COVID illness has resolved. We agree with the authors that persistent radiographic abnormalities are an adverse outcome of COVID that deserve future study, but we disagree with their proposed classification of patterns. We believe that recognition of fibrotic interstitial lung abnormalities (ILAs), as opposed to non-fibrotic ILAs, help prognosticate which abnormalities are less likely to resolve over time (2). Han et al (3) recently demonstrated that individuals with post-COVID fibrotic ILAs at six months had persistent fibrosis at 1-year, suggesting that fibrotic ILAs rarely resolve completely. Ultimately, serial imaging, quantitative measures of fibrosis (4), and assessment of pharmaceutical interventions (5), will be key to fully understanding the trajectory of post-COVID fibrosis.
Secondly, the authors report that disease severity did not significantly impact the development of particular parenchymal abnormalities on CT scan. The authors do not provide analyses in their study to support this statement. Their cohort was sampled from survivors with a persistent need for oxygen therapy, was not sampled randomly from the larger acute COVID population, and only included two subjects who required invasive mechanical ventilation. While we agree that an interplay of many factors contribute to pattern and extent of parenchymal lung disease, we believe that greater severity of illness, as determined by need for invasive mechanical ventilation, should be recognized as a risk factor for persistent fibrotic abnormalities. This conclusion is supported by our study as well as others (1, 6, 7).
Claire McGroder, MD
Mary Salvatore, MD
Eric A. Hoffman, PhD
Matthew Baldwin, MD
Christine Kim Garcia, MD, PhD
REFERENCES
1. McGroder CF, Zhang D, Choudhury MA, Salvatore MM, D'Souza BM, Hoffman EA, Wei Y, Baldwin MR, Garcia CK. Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax 2021.
2. Putman RK, Gudmundsson G, Axelsson GT, Hida T, Honda O, Araki T, Yanagawa M, Nishino M, Miller ER, Eiriksdottir G, Gudmundsson EF, Tomiyama N, Honda H, Rosas IO, Washko GR, Cho MH, Schwartz DA, Gudnason V, Hatabu H, Hunninghake GM. Imaging Patterns Are Associated with Interstitial Lung Abnormality Progression and Mortality. Am J Respir Crit Care Med 2019; 200: 175-183.
3. Han X, Fan Y, Alwalid O, Zhang X, Jia X, Zheng Y, Shi H. Fibrotic Interstitial Lung Abnormalities at 1-year Follow-up CT after Severe COVID-19. Radiology 2021; 301: E438-E440.
4. Nagpal P, Motahari A, Gerard SE, Guo J, Reinhardt JM, Comellas AP, Hoffman EA, Kaczka DW. Case Studies in Physiology: Temporal Variations of the Lung Parenchyma and Vasculature in Asymptomatic COVID-19 Pneumonia: A Multi-Spectral CT Assessment. J Appl Physiol (1985) 2021.
5. Myall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, Preston R, Thillai M, Dewar A, Molyneaux PL, West AG. Persistent Post-COVID-19 Inflammatory Interstitial Lung Disease: An Observational Study of Corticosteroid Treatment. Ann Am Thorac Soc 2021.
6. Francone M, Iafrate F, Masci GM, Coco S, Cilia F, Manganaro L, Panebianco V, Andreoli C, Colaiacomo MC, Zingaropoli MA, Ciardi MR, Mastroianni CM, Pugliese F, Alessandri F, Turriziani O, Ricci P, Catalano C. Chest CT score in COVID-19 patients: correlation with disease severity and short-term prognosis. Eur Radiol 2020; 30: 6808-6817.
7. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, Li Y, Cao Y, Gu J, Wu H, Shi H. Six-month Follow-up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology 2021; 299: E177-E186.
We thank Nimmo et al for their comments on our paper, and for recognising that this work
addresses an important gap in high quality data on aerosol generation and also the technical
challenges associated with measuring aerosol from the respiratory tract.
We agree that interparticipant variability in aerosol emission is significant (spanning several orders
of magnitude) and acknowledge in the paper that interpretation of the data on patients with COVID-
19 is limited due to the small cohort size. The AERATOR study was the first group to collect detailed
aerosol measures from patients with active SARS-CoV-2, the aim of this exploratory sub group
analysis was to consider if active infection had a meaningful impact on the use of healthy controls as
proxies in the main analysis.
Measuring aerosol emission from patients with COVID-19 is very challenging in the acute clinical
setting because of both the very low aerosol background concentration required to make a
measurement and infection control precautions. We therefore chose to report the raw data while
acknowledging the difficulties in interpretation.
In this analysis, we did not perform a sample size calculation; as we were limited by both
epidemiological (level of COVID-19 infection in the community) and practical challenges, detailed
below.
Future studies could consider the collection of detailed aerosol measures from patients a...
We thank Nimmo et al for their comments on our paper, and for recognising that this work
addresses an important gap in high quality data on aerosol generation and also the technical
challenges associated with measuring aerosol from the respiratory tract.
We agree that interparticipant variability in aerosol emission is significant (spanning several orders
of magnitude) and acknowledge in the paper that interpretation of the data on patients with COVID-
19 is limited due to the small cohort size. The AERATOR study was the first group to collect detailed
aerosol measures from patients with active SARS-CoV-2, the aim of this exploratory sub group
analysis was to consider if active infection had a meaningful impact on the use of healthy controls as
proxies in the main analysis.
Measuring aerosol emission from patients with COVID-19 is very challenging in the acute clinical
setting because of both the very low aerosol background concentration required to make a
measurement and infection control precautions. We therefore chose to report the raw data while
acknowledging the difficulties in interpretation.
In this analysis, we did not perform a sample size calculation; as we were limited by both
epidemiological (level of COVID-19 infection in the community) and practical challenges, detailed
below.
Future studies could consider the collection of detailed aerosol measures from patients at various
stages of infection (early and late) and respiratory support , but there are technical and practical
challenges which are currently largely insurmountable (patients receiving these therapies are cared
for in acute clinical settings such as shared multiple bedded bays with background aerosol
concentrations too high to obtain an informative measurement). As far as we are aware, no-one has
published data on patients with COVID-19 receiving any form of non-invasive ventilation or HFNO.
However, given that we did not find any aerosol generation during CPAP (a finding consistent with
other, recent papers 1,2 ), the sum of evidence does not suggest that non-invasive respiratory support
increases aerosol emission, independent of other factors.
As both our data and Wilson et al have shown, aerosol emission is, however, related to respiratory
activity, in particular cough. Therefore we have argued exposure to patients acutely unwell with
COVID-19 is the main driver of risk of nosocomial transmission within healthcare settings, rather
than exposure to patients receiving a given form of respiratory support. 3
Our limited data set does suggest that individuals consistently generate similar amounts of aerosol
while performing the same activity. These data are consistent with some very preliminary published
measurements. 4 Further research, which is being undertaken through the UKRI-funded PERFORM
study will clarify what factors influence aerosol emission on an individual and population level.
1. Wilson NM, Marks GB, Eckhardt A, et al. The effect of respiratory activity, non-invasive
respiratory support and facemasks on aerosol generation and its relevance to COVID-19.
Anaesthesia [Internet] 2021;Available from: http://dx.doi.org/10.1111/anae.15475
2. Gaeckle NT, Lee J, Park Y, Kreykes G, Evans MD, Hogan CJ Jr. Aerosol Generation from the
Respiratory Tract with Various Modes of Oxygen Delivery. Am J Respir Crit Care Med
2020;202(8):1115–24.
3. Hamilton F, Arnold D, Bzdek BR, et al. Aerosol generating procedures: are they of relevance for
transmission of SARS-CoV-2? Lancet Respir Med 2021;9(7):687–9.
4. Asadi S, Wexler AS, Cappa CD, Barreda S, Bouvier NM, Ristenpart WD. Aerosol emission and
superemission during human speech increase with voice loudness. Sci Rep 2019;9(1):2348.
The AERATOR study (Hamilton et al) compares and quantifies the risk of aerosol generation in both healthy patients and those infected with COVID-19 in a variety of contexts, including normal respiration, speaking and coughing, and the same activities whilst receiving therapy with continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO), and also whilst wearing a fluid-resistant surgical mask (FSRM)1. This study is particularly welcome as it is an area where data are scarce, yet the theoretical risks have major implications for both patients and health care professionals and influence recommendations that guide patient care, such as the use of side rooms and personal protective equipment, both of which are limited resources2. However, we have some questions about the study design.
Hamilton et al demonstrated that the size of aerosols generated by healthy individuals and those infected with COVID-19 were comparable, thereby validating the use of healthy volunteers for aerosol characterisation, though the sample sizes involved within the COVID-19 cohort were relatively small (n=6). Furthermore, the study highlights that aerosolisation was lower in healthy volunteers with non-humidified CPAP, whilst it was increased in those receiving HFNO (though it was shown to originate mostly from the device), compared to baseline for breathing, speaking, and coughing. Given the study also mentions a considerable degree of inter- and intra-individual variability...
The AERATOR study (Hamilton et al) compares and quantifies the risk of aerosol generation in both healthy patients and those infected with COVID-19 in a variety of contexts, including normal respiration, speaking and coughing, and the same activities whilst receiving therapy with continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO), and also whilst wearing a fluid-resistant surgical mask (FSRM)1. This study is particularly welcome as it is an area where data are scarce, yet the theoretical risks have major implications for both patients and health care professionals and influence recommendations that guide patient care, such as the use of side rooms and personal protective equipment, both of which are limited resources2. However, we have some questions about the study design.
Hamilton et al demonstrated that the size of aerosols generated by healthy individuals and those infected with COVID-19 were comparable, thereby validating the use of healthy volunteers for aerosol characterisation, though the sample sizes involved within the COVID-19 cohort were relatively small (n=6). Furthermore, the study highlights that aerosolisation was lower in healthy volunteers with non-humidified CPAP, whilst it was increased in those receiving HFNO (though it was shown to originate mostly from the device), compared to baseline for breathing, speaking, and coughing. Given the study also mentions a considerable degree of inter- and intra-individual variability in aerosol generation, information on sample size calculation may be relevant especially in the COVID-19 group which included only six participants³.
COVID-19 patients included in the study were either on low-flow oxygen or room air suggesting that these patients were suffering a non-severe form of the disease. COVID-19 patients requiring CPAP/HFNO tend to manifest with more respiratory symptoms4, and it is not known if these patients would also yield the same outcome as those with milder illness. Would including patients across the disease severity spectrum strengthen the evidence in order to reappraise current infection control practices?
Furthermore, six healthy volunteers underwent further studies to check reproducibility of aerosol number concentration generated at an interval of one month which showed a better correlation for breathing and only a modest value for speaking and coughing. It is unclear if the given number is sufficient to study the reproducibility of aerosol generation. In addition, the study shows the technical challenges in reliably measuring aerosol number concentration for Covid-19 patients due to background aerosols. So aerosol measurement was possible only during coughing, but not breathing or speaking. Therefore better measuring devices/methods with optimisation for background aerosol concentration to test COVID-19 patients would also be useful.
References :
1.Hamilton FW, Gregson FK, Arnold DT et al. Aerosol emission from the respiratory tract:an analysis of aerosol generation from oxygen delivery systems. Thorax 2021.DOI: 10.1136/thoraxjnl-2021-217577
1.Hamilton FW, Gregson FK, Arnold DT,et al. Aerosol emission from the respiratory tract: an analysis of aerosol generation from oxygen delivery systems. Thorax 2021-217577 Google Scholar Pub Med
2. Public Health England. COVID-19: personal protective equipment use for aerosol generating procedures, 2020. Available: https://www.gov.uk/government/publications/covid-19-personal-protective-... [Accessed 24 Jun 2021].
3. Faber J, Fonseca LM. How sample size influences research outcomes. Dental Press J Orthod. 2014;19(4):27-9 Google Scholar Pub Med
4. Klompas M, Baker MA, Rhee C. Airborne transmission of SARS-CoV-2: theoretical considerations and available evidence. JAMA 2020; 324:441–2. Google Scholar Pub Med
Thank you to the authors for this important and detailed analysis. I write to simply draw attention to a discrepancy, unless I am mistaken, between the ATE frequency rates stated in the abstract and those in the main text.
Abstract: "The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively".
Main text: "The weighted frequency of ATE was 4.0% (95%CI 2.0% to 6.5%, I2 =95%; 19 studies; 8249 patients), including myocardial
infarction/acute coronary syndrome (1.1%, 95%CI 0.2% to 3.0%, I2=96%; 16 studies; 7939 patients), ischaemic stroke (1.6%, 95%CI 1.0% to 2.2%, I2 =93%; 27 studies; 40597 patients) and other ATE (0.9%, 95%CI 0.5% to 1.5%; I2
=84%; 17 studies; 20139 patients)
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of L...
Show MoreWe thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
Show MoreThe state-of-the-art-review by Bridges et al. (1) entitled “Respiratory epithelial responses to SARS-CoV-2 in COVID-19” admirably updates current concepts ranging from bedside observations to cell signaling. The authors emphasize epithelial interferon/cytokine defense in upper airways, where infection starts. Advanced Covid-19 is then depicted involving alveolar and capillary injury with uncontrolled leakage of plasma from the pulmonary microcirculation (1).
The subepithelial microcirculations that carry oxygenized blood to nasal, tracheal, and bronchial mucosae are not mentioned. Yet, infection of these conducting airways causes exudation of plasma proteins with well-known antimicrobial defense capacities. Furthermore, contrasting protein leak at lung injury (1), the airways exudative response reflects well-controlled physiological microvascular-epithelial cooperation (2).
Minimal size-selectivity at exudation of plasma across endothelial-epithelial barriers.
Show MoreObservations in infected airways, allergic disease and mediator challenge demonstrate unfiltered and well-controlled plasma exudation responses in human airways. Lack of size-selectivity means that potent cascade systems (complement, kinin/kallikrein, coagulation) and natural antibodies (IgG,IgM) emerge locally, along with albumin, on engaged airway epithelial sites (3-13). Even cathelicidine, representing antimicrobial peptides, arrives on the affected airway surface exclusively as component of...
The benefits of pulmonary rehabilitation for individuals with chronic respiratory diseases are well-documented1, but referral practices and programme completion have remained challenging. This has been exacerbated by the COVID-19 pandemic and shielding practices. Thus, highlighting the usefulness of developing a robust telerehabilitation programme as a substitute for centre-based programmes. The data gained from Cox et al addresses this area and demonstrates clinically meaningful advantages of telerehabilitation and is warmly welcomed. A detailed breakdown of the costs involved between both arms would be very helpful in assessing an overall equivalence of the two arms.
The CRQ is a validated tool for use in research; however, the use of its dyspnoea domain specifically has been shown to be less reliable in comparative research2. Other tools which may be a useful substitute for this study would be ‘incremental shuttle walking test’3 and ‘St George’s respiratory questionnaire’4.
The number of participants presenting to community healthcare services, and/or those requiring rescue therapy for a mild exacerbation (e.g., antibiotics and/or a short course of corticosteroids) not requiring presentation to a hospital, during the study and follow-up period, may be useful for further assessment of the equivalence of telerehabilitation versus centre-based programmes.
This study provides useful data regarding the potential benefits of incorporating telerehabilita...
Show MoreWe agree with Drs. Moolgavkar and Attanoos that our observation of increased risk of asbestosis unaccompanied by increased risk of mesothelioma among motor vehicle mechanics (Thomsen, 2021) is inconsistent with other studies of chrysotile exposed populations. As we discussed in our paper, mesothelioma ascertainment is highly reliable in Denmark and our mesothelioma findings are consistent with previous studies (DeBono, 2021; Garabrant, 2016; Hessel, 2021; Tomasallo, 2018; Van den Borre, 2015). Thus, we believe our findings are reliable. Conversely, the asbestosis findings raise important questions. A diagnosis of asbestosis can only be made when a clinician believes the patient has been exposed to asbestos. Pulmonary fibrosis in a vehicle mechanic might readily be diagnosed as asbestosis if the clinician was aware of the occupational history and possible presence of asbestos in brakes, clutches, gaskets, or other vehicle parts. Since our comparison subjects held jobs that did not involve obvious asbestos exposure, it is less likely that pulmonary fibrosis would be diagnosed as asbestosis in this group. Moolgavkar and Attanoos suggest that our comparison selection could have led to diagnostic bias if the vehicle mechanics and the comparisons did not have equal probabilities of exposure to asbestos from sources other than friction products. We agree - we reported that the abrupt increase in outpatient clinic diagnosed asbestosis beginning in the mid-2000s is consistent with...
Show MoreThomsen et al’s. (2021)1 suggestion that “asbestosis occurs at cumulative chrysotile exposure levels where mesotheliomas are rare or none were observed…”.to explain the increased risk of asbestosis in the absence of an increased risk of mesothelioma among vehicle mechanics appears implausible for many reasons:
Show Morea. Scientific literature shows that when there is a risk of asbestosis there is also an increased risk of pleural mesothelioma2;
b. Cumulative exposures to chrysotile asbestos sustained by career vehicle mechanics are far below the cumulative asbestos exposures traditionally associated with asbestosis (25 fibre/cc-years) as cited by Thomsen et al.1,3;
c. That chrysotile asbestos, with much shorter biopersistence than amphibole asbestos, is more fibrogenic is biologically implausible, and inconsistent with the studies that show that the degree of lung fibrosis/asbestosis correlates with retained amphibole asbestos content, not chrysotile 3,4.
d. Fibre counts amongst vehicle mechanics with mesothelioma have been found to be either within control reference limits or show increased commercial amphibole asbestos, unrelated to friction exposures 2.
e. Animal studies do not report asbestosis or mesothelioma following high-dose inhalation exposures to brake dust with and without added chrysotile 5.
We consider, as Thomsen et al 1 did, that the most plausible explanation is diagnostic bias based on control selection.
In Thomsen et al...
We thank A. Raja and colleagues for their interest in our article on risk factors for fibrotic-like changes after severe COVID-19 infection (1). We agree that identification and management of post-COVID fibrosis continues to be impeded by the lack of consensus definitions and we look forward to further studies that help describe the natural history of post-COVID pulmonary manifestations.
The authors propose that lung fibrosis be classified into different ILDs by the pattern of lung parenchymal abnormalities six months after the initial COVID illness has resolved. We agree with the authors that persistent radiographic abnormalities are an adverse outcome of COVID that deserve future study, but we disagree with their proposed classification of patterns. We believe that recognition of fibrotic interstitial lung abnormalities (ILAs), as opposed to non-fibrotic ILAs, help prognosticate which abnormalities are less likely to resolve over time (2). Han et al (3) recently demonstrated that individuals with post-COVID fibrotic ILAs at six months had persistent fibrosis at 1-year, suggesting that fibrotic ILAs rarely resolve completely. Ultimately, serial imaging, quantitative measures of fibrosis (4), and assessment of pharmaceutical interventions (5), will be key to fully understanding the trajectory of post-COVID fibrosis.
Secondly, the authors report that disease severity did not significantly impact the development of particular parenchymal abnormalities on CT...
Show MoreWe thank Nimmo et al for their comments on our paper, and for recognising that this work
Show Moreaddresses an important gap in high quality data on aerosol generation and also the technical
challenges associated with measuring aerosol from the respiratory tract.
We agree that interparticipant variability in aerosol emission is significant (spanning several orders
of magnitude) and acknowledge in the paper that interpretation of the data on patients with COVID-
19 is limited due to the small cohort size. The AERATOR study was the first group to collect detailed
aerosol measures from patients with active SARS-CoV-2, the aim of this exploratory sub group
analysis was to consider if active infection had a meaningful impact on the use of healthy controls as
proxies in the main analysis.
Measuring aerosol emission from patients with COVID-19 is very challenging in the acute clinical
setting because of both the very low aerosol background concentration required to make a
measurement and infection control precautions. We therefore chose to report the raw data while
acknowledging the difficulties in interpretation.
In this analysis, we did not perform a sample size calculation; as we were limited by both
epidemiological (level of COVID-19 infection in the community) and practical challenges, detailed
below.
Future studies could consider the collection of detailed aerosol measures from patients a...
The AERATOR study (Hamilton et al) compares and quantifies the risk of aerosol generation in both healthy patients and those infected with COVID-19 in a variety of contexts, including normal respiration, speaking and coughing, and the same activities whilst receiving therapy with continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO), and also whilst wearing a fluid-resistant surgical mask (FSRM)1. This study is particularly welcome as it is an area where data are scarce, yet the theoretical risks have major implications for both patients and health care professionals and influence recommendations that guide patient care, such as the use of side rooms and personal protective equipment, both of which are limited resources2. However, we have some questions about the study design.
Hamilton et al demonstrated that the size of aerosols generated by healthy individuals and those infected with COVID-19 were comparable, thereby validating the use of healthy volunteers for aerosol characterisation, though the sample sizes involved within the COVID-19 cohort were relatively small (n=6). Furthermore, the study highlights that aerosolisation was lower in healthy volunteers with non-humidified CPAP, whilst it was increased in those receiving HFNO (though it was shown to originate mostly from the device), compared to baseline for breathing, speaking, and coughing. Given the study also mentions a considerable degree of inter- and intra-individual variability...
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