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)
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
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.
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al....
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6(2):117-26.
3. Linch SN, Kelly AM, Danielson ET, Pero R, Lee JJ, Gold JA. Mouse eosinophils possess potent antibacterial properties in vivo. Infection and immunity. 2009;77(11):4976-82.
We thank James R Camp for his response and interest in our study. To answer the question posed directly, we did not use blood eosinophils as a covariate in the model, since leukocyte differential count is not routinely made at every outpatient visit for COPD patients in Denmark.
The relation between blood eosinophils in COPD and pulmonary infections is not a trivial one. As mentioned by James R Camp, mouse models indicate that eosinophils have antibacterial properties in vitro (1). However, few clinical studies have included blood eosinophil counts as a risk factor of pneumonia in COPD, mostly showing either a weak or no association (2,3).
Eosinophils from human blood have been demonstrated to have bactericidal effects against S. aureus and E. coli, but noteworthy, this effect was not as potent as the neutrophils (4). Additionally, severe acute bacterial infection like sepsis almost uniformly causes eosinopenia (5,6) and experimental lipopolysaccharide injection in healthy humans and diabetic humans cause profound and long-lasting eosinopenia (7). This is not easily comprehensible if the eosinophils are a needed part of the innate host immune response to bacterial infection.
An alternative explanation for a possible association could be that eosinophils and neutrophils act in bacterial infection in a complex interplay, while regulating and adjusting the response of each other. To support this, it has been demonstrated that integrin β chain-2 (CD18),...
We thank James R Camp for his response and interest in our study. To answer the question posed directly, we did not use blood eosinophils as a covariate in the model, since leukocyte differential count is not routinely made at every outpatient visit for COPD patients in Denmark.
The relation between blood eosinophils in COPD and pulmonary infections is not a trivial one. As mentioned by James R Camp, mouse models indicate that eosinophils have antibacterial properties in vitro (1). However, few clinical studies have included blood eosinophil counts as a risk factor of pneumonia in COPD, mostly showing either a weak or no association (2,3).
Eosinophils from human blood have been demonstrated to have bactericidal effects against S. aureus and E. coli, but noteworthy, this effect was not as potent as the neutrophils (4). Additionally, severe acute bacterial infection like sepsis almost uniformly causes eosinopenia (5,6) and experimental lipopolysaccharide injection in healthy humans and diabetic humans cause profound and long-lasting eosinopenia (7). This is not easily comprehensible if the eosinophils are a needed part of the innate host immune response to bacterial infection.
An alternative explanation for a possible association could be that eosinophils and neutrophils act in bacterial infection in a complex interplay, while regulating and adjusting the response of each other. To support this, it has been demonstrated that integrin β chain-2 (CD18), an important component in the cellular adhesion and cell-surface signalling in bacterial infection, can downregulate eosinophil chemotaxis (8).
Human data from randomised controlled trials are necessary to help unravel this. We did, in fact, at an earlier occasion, conduct a large scale randomised controlled trial, the CORTICO-COP trial (9), in which COPD-patients with severe acute exacerbation, were randomly allocated to either a corticosteroid sparing regimen, or a standard regimen with a 5-day-course of oral corticosteroids. This resulted in approximately 60% lower use of corticosteroids, and the eosinophil suppression in this study differed between the two groups: median (IQR); 0.06 (0.09-0.21) vs. 0.10 (0.14-0.34), p<0.0001). Thus, if eosinophils had an important role in the bacterial host immune response, we would have expected patients in the “low eosinophil group” to have a worse clinical course. This was not the case, since no difference in any clinical outcomes was observed. Moreover, there were no significant association between bacterial infection and treatment group or eosinophil count. Similarly, a large randomised controlled trial of hospitalised patients with community-aquired pneumonia has reported significantly shorter time to clinical stability and shorter hospital stay with adjunct prednisone treatment compared to placebo (10), despite the expected corticosteroid-induced eosinophil suppression in the intervention group.
To summarise, there are so far no solid clinical data supporting an important antibacterial effect of eosinophils, although some laboratory data support this. To return to the point of John R. Camp, we find it unlikely that adjusting our data for eosinophil counts would alter the signal of our study.
1. Linch SN, Kelly AM, Danielson ET, Pero R, Lee JJ, Gold JA. Mouse eosinophils possess potent antibacterial properties in vivo. Infection and immunity. 2009;77(11):4976-82.
2. Pascoe S, Barnes N, Brusselle G, Compton C, Criner GJ, Dransfield MT, Halpin DMG, Han MK, Hartley B, Lange P, Lettis S, Lipson DA, Lomas DA, Martinez FJ, Papi A, Roche N, van der Valk RJP, Wise R, Singh D. Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Lancet Respir Med. 2019 Sep;7(9):745-756. doi: 10.1016/S2213-2600(19)30190-0. Epub 2019 Jul 4. PMID: 31281061.
3. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med. 2016 Sep;4(9):731-741.
4. Yazdanbakhsh M, Eckmann CM, Bot AA, Roos D. Bactericidal action of eosinophils from normal human blood. Infect Immun. 1986 Jul;53(1):192-8.
5. Bass DA. Behavior of eosinophil leukocytes in acute inflammation. II. Eosinophil dynamics during acute inflammation. J Clin Invest. 1975 Oct;56(4):870-9.
7. Gilbert HS, Rayfield EJ, Smith H Jr, Keusch GT. Effects of acute endotoxemia and glucose administration on circulating leukocyte populations in normal and diabetic subjects. Metabolism. 1978 Aug;27(8):889-99.
8. Nagata M, Sedgwick JB, Busse WW. Differential effects of granulocyte-macrophage colony-stimulating factor on eosinophil and neutrophil superoxide anion generation. J Immunol. 1995 Nov 15;155(10):4948-54.
9. Sivapalan P, Lapperre TS, Janner J, Laub RR, Moberg M, Bech CS, Eklöf J, Holm FS, Armbruster K, Sivapalan P, Mosbech C, Ali AKM, Seersholm N, Wilcke JT, Brøndum E, Sonne TP, Rønholt F, Andreassen HF, Ulrik CS, Vestbo J, Jensen JS. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019 Aug;7(8):699-709.
10. Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, Winzeler B, Bingisser R, Elsaesser H, Drozdov D, Arici B, Urwyler SA, Refardt J, Tarr P, Wirz S, Thomann R, Baumgartner C, Duplain H, Burki D, Zimmerli W, Rodondi N, Mueller B, Christ-Crain M. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2015 Apr 18;385(9977):1511-8.
Letter to the editor:
We appreciate the opportunity to comment on the article by Thomsen RW et al. Risk of asbestos, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. We believe there are many problems in methodology and we disagree with author’s interpretations and conclusions especially in relation to asbestos and mesothelioma in vehicle mechanics in this article.
The epidemiology analysis described by Thomsen et al lacks asbestos exposure data and uses cross-sectional occupation data as surrogates for longitudinal use. Occupational categories are not equal to exposure. Especially for asbestos it has been clear that obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease. Without longitudinal individual exposure histories in the Thomson et al study, there is undoubtably significant misclassification of exposure in both the motor vehicle mechanic group (unexposed considered exposed) and even more problematic in the control group (exposed classified as unexposed). This double likelihood of exposure misclassification creates unreliable analytics which result in an epidemiologic bias towards the null. 1
Thomsen et al used cross-sectional data at variable dates to place workers in their two study cohorts based on reported current occupation and industry. The occupation on the 1970 census or when first...
Letter to the editor:
We appreciate the opportunity to comment on the article by Thomsen RW et al. Risk of asbestos, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. We believe there are many problems in methodology and we disagree with author’s interpretations and conclusions especially in relation to asbestos and mesothelioma in vehicle mechanics in this article.
The epidemiology analysis described by Thomsen et al lacks asbestos exposure data and uses cross-sectional occupation data as surrogates for longitudinal use. Occupational categories are not equal to exposure. Especially for asbestos it has been clear that obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease. Without longitudinal individual exposure histories in the Thomson et al study, there is undoubtably significant misclassification of exposure in both the motor vehicle mechanic group (unexposed considered exposed) and even more problematic in the control group (exposed classified as unexposed). This double likelihood of exposure misclassification creates unreliable analytics which result in an epidemiologic bias towards the null. 1
Thomsen et al used cross-sectional data at variable dates to place workers in their two study cohorts based on reported current occupation and industry. The occupation on the 1970 census or when first mentioned for individuals on later registrations was used to assign vehicle mechanic occupation with the assumption that asbestos exposure had occurred. The selected occupation categories for the “comparison” cohort assumed non-asbestos exposed occupations throughout their working lifetime. Other than looking for the vehicle mechanic category, apparently no search was made in subsequent registries to see if they had switched to another occupation with asbestos exposure likelihood. The authors do mention that about one half of the 21,102 1970 census vehicle mechanic individuals were in the same category in the 1996-1999 registry. However, was the work they performed the same? The cohort was very young at entrance at any of the time intervals (median age 25) and the median follow-up was 20 years. The age at which mesothelioma occurs is usually in the 70+ age group. Latency for mesothelioma can be as high as 50 years or more. Over 70% of the cohort were first enrolled after 1986 when asbestos use in Danish vehicle brakes was disappearing, exposure standards in place and the likelihood of high exposure for those just entering the cohort reduced. Only 23% of the cohort was deceased and the vast majority had not reached the age group where mesotheliomas or asbestosis would occur, given their long latent period.
The overall finding of Thomsen et al was that asbestosis was elevated in motor vehicle mechanics, but not mesothelioma. A clinical diagnosis of asbestosis requires a history of asbestos exposure while at autopsy a tissue diagnosis may be made when no exposure history is found. What is striking is that there were 313 comparator cases of asbestosis in the morbidity data and 108 in mortality. This information supports the case for exposure misclassification in the comparison group. Similarly, the occurrence of 553 mesothelioma/pleural cancer mortality cases among the comparators and 628 cases in the morbidity files also suggests misclassification among the “non-asbestos exposed” as an explanation for the lack of statistical differences between the cohorts.
The high number of asbestosis cases and deaths among the comparison group and the statistical excess among the vehicle mechanics but not an excess of mesothelioma/pleural cancer is puzzling as a higher dose of asbestos exposure is needed for asbestosis than for mesothelioma.2 An explanation may be that the years of follow-up in the Thomsen et al study may not have been long enough for the peak mesothelioma risk but sufficient for clinical detection of asbestosis/pleural abnormalities. Supporting this is that Thomsen et al found the highest association with mesothelioma in the 1970 census cohort, which had the longest follow-up.
Thomsen et al. states that asbestos use in brakes is now phased out in most countries. Unfortunately, this is not true. Chrysotile asbestos is currently being widely used in Brazil, Russia, China, India, Thailand, Malaysia and elsewhere and is being used in the manufacture of brakes. (2-5) Since there is potential exposure to toxic chrysotile asbestos fibers of various sizes in the dusty environment of motor vehicle mechanics, which is continuing in several countries around the world, precaution should point to policies that concentrate on industrial hygiene measures that limit worker dust exposure.
Marty S Kanarek, PhD1, Henry A Anderson, MD1
1 Department of Population Health Sciences and in the Nelson Institute for Environmental Studies, University of Wisconsin-Madison, Madison, Wisconsin, USA
Correspondence to Professor Marty Kanarek, Department of Population Health Sciences, School of Medicine and Public Health, 610 N. Walnut Street, University of Wisconsin-Madison, 53726; mkanarek@wisc.edu
Contributors MSK was the lead author. HAA was co-author, reviewing the original response and contributing original content in addition to editing. Final version was approved by both authors.
Funding None
Competing interests Both Kanarek and Anderson have served as consultants to government and international agencies on asbestos health effects, and have been consultants and witnesses on plaintiff’s litigation concerning asbestos and disease.
References
1. Checkoway H, Pearce N, Kriebel D. Research methods in occupational epidemiology. Monographs in Epidemiology, 2nd Ed. 2004, Oxford U Press.
2. Kanarek, MS, Anderson HA. Mesothelioma from asbestos exposure in brake mechanics: epidemiology in context. Epidemiology: Open Access 2018;8:2. DOI. 10.4172/2161-1165.1000340.
3. Kunpeuk W, Sataporn J, Mathudara P1, Jeerapa S1, et al
A scoping review on occupational exposure of silica and asbestos among
industrial workers in Thailand. Outbreak, Surveillance Investigation and Response OSIR Journal , 2021, Volume 14, Issue 2:.41-51.
4. Chen T, Xiao-Ming S, Wu L. High time for complete ban on asbestos use
in developing countries. JAMA Oncology 2019; May 23 E1-E2.
5. Omar A, Lamin F , Mohamed N. Comparative study of brake pads in Malaysian
automotive aftermarket. International Journal of Crashworthiness 2016; http://dx.doi.org/10.1080/13588265.2016.1221372.
We appreciate the thoughtful letter from Drs. Kanarek and Anderson. Our study does not address the well-established fact that asbestos exposure is the main causal factor of mesothelioma. The objective of our study was to investigate the risk of mesothelioma (and other asbestos related diseases) in motor vehicle mechanics. The key finding is that Danish motor vehicle mechanics do not on average have an elevated risk of mesothelioma during the studied up to 45 years of follow-up. This does not exclude the possibility that some subpopulations of motor vehicle mechanics with more extreme exposure/latency time are at increased risk – but this occupation as a group is not.
We agree that exposure misclassification is a potential problem in epidemiology studies based on occupation and industry titles. We also agree that lifetime asbestos exposure histories, if they could be obtained, might reduce exposure misclassification. However, asbestos exposure is often not recognized or recalled by workers, and workers often do not recall jobs in the distant past. Also, experts may misclassify self-reported jobs regarding asbestos exposure, particularly with respect to asbestos fiber type. Thus, while Drs. Kanarek and Anderson claim “obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease” they offer no practical advice on how reliable asbestos exposure histories can be obtained. They also...
We appreciate the thoughtful letter from Drs. Kanarek and Anderson. Our study does not address the well-established fact that asbestos exposure is the main causal factor of mesothelioma. The objective of our study was to investigate the risk of mesothelioma (and other asbestos related diseases) in motor vehicle mechanics. The key finding is that Danish motor vehicle mechanics do not on average have an elevated risk of mesothelioma during the studied up to 45 years of follow-up. This does not exclude the possibility that some subpopulations of motor vehicle mechanics with more extreme exposure/latency time are at increased risk – but this occupation as a group is not.
We agree that exposure misclassification is a potential problem in epidemiology studies based on occupation and industry titles. We also agree that lifetime asbestos exposure histories, if they could be obtained, might reduce exposure misclassification. However, asbestos exposure is often not recognized or recalled by workers, and workers often do not recall jobs in the distant past. Also, experts may misclassify self-reported jobs regarding asbestos exposure, particularly with respect to asbestos fiber type. Thus, while Drs. Kanarek and Anderson claim “obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease” they offer no practical advice on how reliable asbestos exposure histories can be obtained. They also provide no evidence that such histories can differentiate between chrysotile and amphibole fibers, and provide no evidence that exposure misclassification from such histories would be less than from the methods we used.
We note that Dr. Anderson and colleagues recently published a study of mesothelioma incidence and mortality in Wisconsin (1) that identified asbestos-exposed occupations based on the self-reported “longest held job reported at the time of diagnosis” or the “usual industry and occupation” recorded on death certificates for mesothelioma cases. It was noted in that paper, that the authors were unable “to determine occupational exposure to asbestos that may have occurred from other work periods” and could not “identify nonoccupational exposure to asbestos.” Dr. Anderson acknowledged that “we would expect any bias introduced to be toward the null and lead to more conservative estimates of effect.” We believe that occupational histories in our study, which were based on historic, written employment records gathered in independent, population-based registers, were far more reliable than the self-reported usual occupations in Dr. Anderson et al.’s study.
There are now over 30 published studies of mesothelioma risks among automobile mechanics, only one of which found increased risk of mesothelioma in which the 95% confidence interval excluded the null, and which otherwise show no increased risk of mesothelioma among automobile mechanics. The consistency of these results observed by different persons, in different places, circumstances, and times (2) (some of which had lifetime occupational and environmental asbestos exposure histories) is a strong argument against the premise that exposure misclassification substantially biased the results.
Dr. Kanarek recently published a review paper in which he reported “There have not been definitive epidemiology studies of brake mechanics because of the nature of the workforce. It is generally nonunionized and spread out in car repair shops” and “Exposure to asbestos from brakes can occur to automobile or truck mechanics anywhere in a vehicle repair shop and the workers are highly transient and not documented.” Dr. Kanarek also noted there have not been “any prospective cohort studies conducted on a group of automobile mechanics.” (3). We believe our study, which is a prospective cohort study based on documented work in vehicle repair shops, answers many of his concerns.
Drs. Kanarek and Anderson point out that over 70% of our cohort of vehicle mechanics were first enrolled after 1986 when asbestos use in Danish vehicle brakes was disappearing. While this statement is correct, it ignores that 21,102 of our subjects were enrolled as mechanics in the 1970 nationwide census and that they were followed through 2015. Moreover, many of them were mechanics prior to the 1970 census. This is substantial number of people followed for a long time, regardless of whether they made up a small proportion of our entire study population. Selikoff’s landmark study of insulators (4) included only 17,800 workers, the majority of whom had yet to achieve 20 years from first exposure at the start of the study, and who were followed for only 10 years. Our population exceeded all these metrics: it was adequate to detect a substantial risk increase of mesothelioma, had there been one. Kanarek and Anderson recognize that our study was adequate to report a significant excess of asbestosis, even though there were fewer asbestosis deaths (19) than there were mesothelioma deaths (48) and the same numbers of incident cases of asbestosis cases (47) as mesotheliomas (47). This is again evidence that our study was adequate to find excess risks of both asbestosis and mesothelioma when they existed.
Drs. Kanarek and Anderson suggest that observing 313 cases of asbestosis in comparators supports the case for exposure misclassification in the comparison group. While it is possible that a small proportion of the 845,480 comparators (who functioned as 1,385,590 comparators after matching with replacement) may have had asbestos exposure at some point in their lives, the more appropriate conclusion is that the comparators were extremely unlikely to be diagnosed with asbestosis (incidence rate 1.19 per 100,000 person-years) or die of asbestosis (mortality rate 0.42 per 100,000 person years), and that not all cases of asbestosis (or mesothelioma) are caused by known exposure to asbestos. We believe a strength of our study was the choice of comparator occupations: we chose those that would be unlikely to have occupational asbestos exposure and that would have no overlapping skills with typical asbestos exposed jobs (such as in shipyards, construction, insulators, plumbing, etc.)
We acknowledge that asbestos is still used in several countries and that that these exposures should be eliminated. The findings in our paper cannot and should not be taken as an argument not to pursue this goal. We thank Drs. Anderson and Kanarek for facilitating a more thorough discussion of these issues.
References cited
1) 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.
2) Hill AB. The environment and disease: association or causation. Proceedings of the Royal Society of Medicine. 1965;58:295-300.
3) Kanarek MS, Anderson HA. Mesothelioma from Asbestos Exposure in Brake Mechanics: Epidemiology in Context. Epidemiology (Sunnyvale). 2018;8(1):12.
4) Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer. 1980;46:2736-40.
Hessel(1) published an editorial concerning mesothelioma among vehicle mechanics and concluded that ‘with nearly two dozen studies of mesothelioma among vehicle mechanics and no evidence of increased risk, it would appear obvious that vehicle mechanics as an occupational group, are not at increased risk of mesothelioma.’ In my opinion Hessel relies too heavily upon epidemiology for his conclusions. Epidemiology is important if studies reliably address the question at issue, but published epidemiologic studies are generally not helpful to the evaluation of risk among vehicle mechanics. Few were designed to be studies of mesothelioma in mechanics. Most are general studies of the disease Mesothelioma in which some of the subjects happened to be mechanics. Since they were not designed to be studies of vehicle mechanics, none of the information necessary for a study of risk, such as the numbers of brake jobs performed, the use of compressed air, sanding or grinding, was collected. Not a single one of the studies had information adequate to compute a quantitative exposure estimate for any of the subjects. Misclassification of exposures will mask risk among those truly exposed(2,3).
Hessel suggests that the paper in Thorax by Thomsen (4) supports his opinion. The aim of that paper was to compare risk among men in a cohort of vehicle mechanics with a comparison cohort of men not occupationally exposed to asbestos. When studying risk in a population exposed to a toxic subs...
Hessel(1) published an editorial concerning mesothelioma among vehicle mechanics and concluded that ‘with nearly two dozen studies of mesothelioma among vehicle mechanics and no evidence of increased risk, it would appear obvious that vehicle mechanics as an occupational group, are not at increased risk of mesothelioma.’ In my opinion Hessel relies too heavily upon epidemiology for his conclusions. Epidemiology is important if studies reliably address the question at issue, but published epidemiologic studies are generally not helpful to the evaluation of risk among vehicle mechanics. Few were designed to be studies of mesothelioma in mechanics. Most are general studies of the disease Mesothelioma in which some of the subjects happened to be mechanics. Since they were not designed to be studies of vehicle mechanics, none of the information necessary for a study of risk, such as the numbers of brake jobs performed, the use of compressed air, sanding or grinding, was collected. Not a single one of the studies had information adequate to compute a quantitative exposure estimate for any of the subjects. Misclassification of exposures will mask risk among those truly exposed(2,3).
Hessel suggests that the paper in Thorax by Thomsen (4) supports his opinion. The aim of that paper was to compare risk among men in a cohort of vehicle mechanics with a comparison cohort of men not occupationally exposed to asbestos. When studying risk in a population exposed to a toxic substance one could ask: (1) How does the disease risk in this population compare to the disease risk in another population also exposed to this toxic substance? Or, (2) How does the risk in this population compare with the risk in an unexposed population? Thomsen wrote “the IR of mesothelioma in our comparison workers was 2.39 per 100 000 person-years, 31% of the IR among Danish men of the same median age, suggesting that our controls were less likely to have been exposed to asbestos than the general population of Danish men.” Thomsen thus addressed question (1) “How does the disease risk among vehicle mechanics compare to the disease risk in another population also exposed to asbestos?” They showed that the risk of mesothelioma among mechanics was less than the risk of mesothelioma in a population of subjects with asbestos exposure sufficient to cause asbestosis in some one in 2500 subjects. They have not demonstrated absence of risk in comparison to the unexposed.
Reference List
1. Hessel PA. Mesothelioma among vehicle mechanics: a controversy? Thorax. 2021.
2. Teschke K. Thinking about Occupation-Response and Exposure-Response Relationships: Vehicle Mechanics, Chrysotile, and Mesothelioma. Ann Occup Hyg. 2016;60:528-530.
3. Van den Borre L, Deboosere P. Asbestos in Belgium: an underestimated health risk. The evolution of mesothelioma mortality rates (1969-2009). Int J Occup Environ Health. 2014;20:134-140.
4. Thomsen RW, Riis AH, Flachs EM, Garabrant DH, Bonde JPE, Sorensen HT. Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. Thorax. 2021.
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 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.
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)
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 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...
We recently read the recent publication by Elköf and colleagues in the recent issue of Thorax titled ‘Use of inhaled corticosteroids and risk of acquiring Pseudomonas aeruginosa in patients with chronic obstructive pulmonary disease’(1) with great interest. The paper highlights an important clinical observation in a well-defined cohort.
We were interested that Elköf and colleagues, tentatively discuss that biological mechanisms resulting from ICS alterations on the immune system may be an explanation for a change in the microbial composition in the airways(1). As the authors discussed, eosinophilic inflammation in COPD identifies a group of patients with ICS responsiveness(2). In the mouse model, there are data examining that eosinophils have anti-microbial properties(3). Access to eosinophil counts from this cohort may be invaluable in unravelling the relationship of eosinophils and COPD and could provide insight into the impact of steroids in bacterial infection. Did the authors investigate the peripheral blood eosinophil count as a covariate in their main analyses?
References
1. Eklöf J, Ingebrigtsen TS, Sørensen R, Saeed MI, Alispahic IA, Sivapalan P, et al. Use of inhaled corticosteroids and risk of acquiring <em>Pseudomonas aeruginosa</em> in patients with chronic obstructive pulmonary disease. Thorax. 2021:thoraxjnl-2021-217160.
Show More2. Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al....
We thank James R Camp for his response and interest in our study. To answer the question posed directly, we did not use blood eosinophils as a covariate in the model, since leukocyte differential count is not routinely made at every outpatient visit for COPD patients in Denmark.
The relation between blood eosinophils in COPD and pulmonary infections is not a trivial one. As mentioned by James R Camp, mouse models indicate that eosinophils have antibacterial properties in vitro (1). However, few clinical studies have included blood eosinophil counts as a risk factor of pneumonia in COPD, mostly showing either a weak or no association (2,3).
Eosinophils from human blood have been demonstrated to have bactericidal effects against S. aureus and E. coli, but noteworthy, this effect was not as potent as the neutrophils (4). Additionally, severe acute bacterial infection like sepsis almost uniformly causes eosinopenia (5,6) and experimental lipopolysaccharide injection in healthy humans and diabetic humans cause profound and long-lasting eosinopenia (7). This is not easily comprehensible if the eosinophils are a needed part of the innate host immune response to bacterial infection.
An alternative explanation for a possible association could be that eosinophils and neutrophils act in bacterial infection in a complex interplay, while regulating and adjusting the response of each other. To support this, it has been demonstrated that integrin β chain-2 (CD18),...
Show MoreLetter to the editor:
We appreciate the opportunity to comment on the article by Thomsen RW et al. Risk of asbestos, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study. We believe there are many problems in methodology and we disagree with author’s interpretations and conclusions especially in relation to asbestos and mesothelioma in vehicle mechanics in this article.
The epidemiology analysis described by Thomsen et al lacks asbestos exposure data and uses cross-sectional occupation data as surrogates for longitudinal use. Occupational categories are not equal to exposure. Especially for asbestos it has been clear that obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease. Without longitudinal individual exposure histories in the Thomson et al study, there is undoubtably significant misclassification of exposure in both the motor vehicle mechanic group (unexposed considered exposed) and even more problematic in the control group (exposed classified as unexposed). This double likelihood of exposure misclassification creates unreliable analytics which result in an epidemiologic bias towards the null. 1
Thomsen et al used cross-sectional data at variable dates to place workers in their two study cohorts based on reported current occupation and industry. The occupation on the 1970 census or when first...
Show MoreWe appreciate the thoughtful letter from Drs. Kanarek and Anderson. Our study does not address the well-established fact that asbestos exposure is the main causal factor of mesothelioma. The objective of our study was to investigate the risk of mesothelioma (and other asbestos related diseases) in motor vehicle mechanics. The key finding is that Danish motor vehicle mechanics do not on average have an elevated risk of mesothelioma during the studied up to 45 years of follow-up. This does not exclude the possibility that some subpopulations of motor vehicle mechanics with more extreme exposure/latency time are at increased risk – but this occupation as a group is not.
We agree that exposure misclassification is a potential problem in epidemiology studies based on occupation and industry titles. We also agree that lifetime asbestos exposure histories, if they could be obtained, might reduce exposure misclassification. However, asbestos exposure is often not recognized or recalled by workers, and workers often do not recall jobs in the distant past. Also, experts may misclassify self-reported jobs regarding asbestos exposure, particularly with respect to asbestos fiber type. Thus, while Drs. Kanarek and Anderson claim “obtaining an individual lifetime occupational and environmental exposure history is crucial to understanding individual work-related causes of disease” they offer no practical advice on how reliable asbestos exposure histories can be obtained. They also...
Show MoreHessel(1) published an editorial concerning mesothelioma among vehicle mechanics and concluded that ‘with nearly two dozen studies of mesothelioma among vehicle mechanics and no evidence of increased risk, it would appear obvious that vehicle mechanics as an occupational group, are not at increased risk of mesothelioma.’ In my opinion Hessel relies too heavily upon epidemiology for his conclusions. Epidemiology is important if studies reliably address the question at issue, but published epidemiologic studies are generally not helpful to the evaluation of risk among vehicle mechanics. Few were designed to be studies of mesothelioma in mechanics. Most are general studies of the disease Mesothelioma in which some of the subjects happened to be mechanics. Since they were not designed to be studies of vehicle mechanics, none of the information necessary for a study of risk, such as the numbers of brake jobs performed, the use of compressed air, sanding or grinding, was collected. Not a single one of the studies had information adequate to compute a quantitative exposure estimate for any of the subjects. Misclassification of exposures will mask risk among those truly exposed(2,3).
Show MoreHessel suggests that the paper in Thorax by Thomsen (4) supports his opinion. The aim of that paper was to compare risk among men in a cohort of vehicle mechanics with a comparison cohort of men not occupationally exposed to asbestos. When studying risk in a population exposed to a toxic subs...
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:
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 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...
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