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
We read with interest McGroder et al’s study on the radiographic findings of patients four months after severe COVID-19 and the associated risk factors. Hürsoy and colleagues’ comment (1) on the paper was equally thought-provoking. We would like to further this discussion by contributing some of our observations from the pulmonology clinic at a major academic medical center in South East Asia.
It has been tremendously challenging globally to achieve precision in the diagnosis of Interstitial Lung Disease (ILD) post-COVID as invasive testing such as lung biopsies are performed sparingly. Histopathological pulmonary findings have largely remained inaccessible since COVID survivors are hypoxic so biopsies pose a high risk for the patient, and healthcare personnels are reluctant to perform such high-risk procedures. Hence, we are left to derive our diagnosis from radiological data and pulmonary function tests (PFTs) of the patient.
We propose that a consensus definition be reached for the diagnosis of post-COVID ILD, one that incorporates well-accepted radiological terms (used to represent any interstitial lung disease). We recommend that lung fibrosis only be classified as ILD if the lung parenchymal abnormalities persist for a minimum of six months after the COVID infection has resolved. Post-COVID ILD should then be further subclassified based on distinct radiological patterns. In our retrospective cohort study, four patterns of post-COV...
We read with interest McGroder et al’s study on the radiographic findings of patients four months after severe COVID-19 and the associated risk factors. Hürsoy and colleagues’ comment (1) on the paper was equally thought-provoking. We would like to further this discussion by contributing some of our observations from the pulmonology clinic at a major academic medical center in South East Asia.
It has been tremendously challenging globally to achieve precision in the diagnosis of Interstitial Lung Disease (ILD) post-COVID as invasive testing such as lung biopsies are performed sparingly. Histopathological pulmonary findings have largely remained inaccessible since COVID survivors are hypoxic so biopsies pose a high risk for the patient, and healthcare personnels are reluctant to perform such high-risk procedures. Hence, we are left to derive our diagnosis from radiological data and pulmonary function tests (PFTs) of the patient.
We propose that a consensus definition be reached for the diagnosis of post-COVID ILD, one that incorporates well-accepted radiological terms (used to represent any interstitial lung disease). We recommend that lung fibrosis only be classified as ILD if the lung parenchymal abnormalities persist for a minimum of six months after the COVID infection has resolved. Post-COVID ILD should then be further subclassified based on distinct radiological patterns. In our retrospective cohort study, four patterns of post-COVID lung parenchymal changes were exhibited by patients with no preexisting lung disease: persistent ground-glass opacities; interlobular septal thickening; reticulation and honeycombing; interlobular septal thickening and reticulations; and patchy consolidation with or without ground-glass opacity (2).
In terms of outcome, within our cohort of severe to critically ill patients, most developed persistent ground-glass opacities or patchy consolidation (with or without ground-glass opacity); a majority of these participants significantly improved (clinically and radiologically) upon administration of corticosteroids (2). Radiological improvement was defined as clearance of at least 50% of lung infiltrates. Reiterating our findings, Han et al. reported ground-glass opacities as the predominant pattern observed in follow-up CT scans of patients with fibrotic-like changes within six months of disease onset (3). Three of the five patients in our study who died had progressive disease with reticulation and honeycombing. To achieve greater accuracy in disease severity assessment and risk stratification, we suggest employing PFTs, particularly to obtain diffusion capacity of the lungs for carbon monoxide (DLCO) and forced vital capacity (FVC) measurements. For the eight out of thirty patients in our cohort who had significant HRCT findings, PFTs were ordered to assess physiological function; three presented with low FVCs (2). In Han et al’s study, abnormal DLCO (less than 80%) at 6-month follow up was a common occurrence in those with fibrotic-like changes (3).
Similar to McGroder et al’s findings, we concluded that the male gender was a significant predisposing factor for post-COVID pulmonary fibrosis. Moreover, like Li et al. and Han et al., we found diabetes mellitus and hypertension to be prevalent comorbidities in patients who developed fibrotic changes (2-4). Interestingly, in our cohort, disease severity did not significantly influence the development of any particular pattern of lung parenchymal abnormality. In light of these observations, we can conclude that the reported lung microstructure changes are not only a ramification of post-ARDS fibrosis or ventilator-induced lung damage but also a consequence of direct virus attack and aberrant local immune response. This is further evidenced by the finding that the Coronavirus induced fibrosis even in moderately ill patients who did not require invasive mechanical ventilation or ICU stay (2).
We hope that prospective studies will further enrich and broaden the global dialogue on post-COVID lung fibrosis.
References:
1. Hürsoy et al. 2021. e-letter https://thorax.bmj.com/eletters
2. Zubairi ABS, Shaikh A, Zubair SM, Ali AS, Awan S, Irfan M. Persistence of post-COVID lung parenchymal abnormalities during the three-month follow-up. Adv Respir Med. 2021;89(5):477–83. Available from: https://pubmed.ncbi.nlm.nih.gov/34612504/
3. Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six-month Follow-up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology. 2021;299(1):E177-E186.
4. Li Y, Wu J, Wang S, Li X, Zhou J, Huang B, et al. Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China. Histopathology. 2021;78(4):542-55.
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.
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.
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 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 N. Hürsoy and colleagues for their interest in our study of patients four months after severe COVID-19 [1]. We agree that there needs to be continued development of terms describing the radiographic appearance of post-COVID fibrotic-like patterns. We acknowledge that without the benefit of histopathology or serial imaging, our ability to define pulmonary fibrosis is limited.
The authors posit that parenchymal bands, irregular densities, and ground glass opacities, may be considered fibrotic-like patterns. We have included irregular densities, characterized as reticulations or traction bronchiectasis, as fibrotic-like changes. We did not include parenchymal bands [2], as these can be associated with atelectasis, which is common in COVID and can disappear over time [3]. Similarly, we did not include isolated ground glass opacities as fibrotic-like changes, as these have been found to decrease over time in CT lung cancer screening cohorts [4] and in other post COVID-19 cohorts [5, 6].
A priori, we evaluated for both previously established interstitial lung abnormality categories [7], as well as categories of radiographic abnormalities reported in Acute Respiratory Distress Syndrome (ARDS) survivors using an established scoring system [8]. This inclusive approach should facilitate meta-analyses and comparisons with future studies of COVID-19 survivors, interstitial lung disease studies, and studies of non-COVID ARDS survivors. Fu...
We thank N. Hürsoy and colleagues for their interest in our study of patients four months after severe COVID-19 [1]. We agree that there needs to be continued development of terms describing the radiographic appearance of post-COVID fibrotic-like patterns. We acknowledge that without the benefit of histopathology or serial imaging, our ability to define pulmonary fibrosis is limited.
The authors posit that parenchymal bands, irregular densities, and ground glass opacities, may be considered fibrotic-like patterns. We have included irregular densities, characterized as reticulations or traction bronchiectasis, as fibrotic-like changes. We did not include parenchymal bands [2], as these can be associated with atelectasis, which is common in COVID and can disappear over time [3]. Similarly, we did not include isolated ground glass opacities as fibrotic-like changes, as these have been found to decrease over time in CT lung cancer screening cohorts [4] and in other post COVID-19 cohorts [5, 6].
A priori, we evaluated for both previously established interstitial lung abnormality categories [7], as well as categories of radiographic abnormalities reported in Acute Respiratory Distress Syndrome (ARDS) survivors using an established scoring system [8]. This inclusive approach should facilitate meta-analyses and comparisons with future studies of COVID-19 survivors, interstitial lung disease studies, and studies of non-COVID ARDS survivors. Furthermore, it allows for future post-hoc analyses if alternate definitions of fibrotic-like patterns in COVID-19 survivors are established. Additionally, we showed that objective quantitative analyses closely agreed with visual assessments (Figure S2). These types of quantitative imaging analyses may facilitate the convergence of data from multiple centers if imaging protocols become more standardized [9].
Efforts are underway to characterize pulmonary impairments and radiographic abnormalities in our cohort over time in order to assess longitudinal evolution. We acknowledge that our findings do not exclude the possibility of pre-existing lung disease and we therefore look forward to reviewing independent studies, such as the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) [10] project, which will provide better understanding of radiographic changes by comparing chest imaging studies before and after SARS-CoV-2 infection.
1. McGroder, C.F., et al., Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax, 2021.
2. Pulmonary Parenchymal Band. Available from: https://www.ncbi.nlm.nih.gov/medgen/978776.
3. Kong, M., et al., Evolution of chest CT manifestations of COVID-19: a longitudinal study. J Thorac Dis, 2020. 12(9): p. 4892-4907.
4. Jin, G.Y., et al., Interstitial lung abnormalities in a CT lung cancer screening population: prevalence and progression rate. Radiology, 2013. 268(2): p. 563-71.
5. Nagpal, P., et al., 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.
6. Liu, D., et al., The pulmonary sequalae in discharged patients with COVID-19: a short-term observational study. Respir Res, 2020. 21(1): p. 125.
7. Hatabu, H., et al., Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. Lancet Respir Med, 2020. 8(7): p. 726-737.
8. Burnham, E.L., et al., Chest CT features are associated with poorer quality of life in acute lung injury survivors. Crit Care Med, 2013. 41(2): p. 445-56.
9. Nagpal, P., et al., Quantitative CT imaging and advanced visualization methods: potential application in novel coronavirus disease 2019 (COVID-19) pneumonia. BJR Open, 2021. 3(1): p. 20200043.
10. Collaborative Cohort of Cohorts for COVID-19 Research. Available from: https://c4r-nih.org/content/overview.
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...
Show MoreDear Editor,
We read with interest McGroder et al’s study on the radiographic findings of patients four months after severe COVID-19 and the associated risk factors. Hürsoy and colleagues’ comment (1) on the paper was equally thought-provoking. We would like to further this discussion by contributing some of our observations from the pulmonology clinic at a major academic medical center in South East Asia.
It has been tremendously challenging globally to achieve precision in the diagnosis of Interstitial Lung Disease (ILD) post-COVID as invasive testing such as lung biopsies are performed sparingly. Histopathological pulmonary findings have largely remained inaccessible since COVID survivors are hypoxic so biopsies pose a high risk for the patient, and healthcare personnels are reluctant to perform such high-risk procedures. Hence, we are left to derive our diagnosis from radiological data and pulmonary function tests (PFTs) of the patient.
We propose that a consensus definition be reached for the diagnosis of post-COVID ILD, one that incorporates well-accepted radiological terms (used to represent any interstitial lung disease). We recommend that lung fibrosis only be classified as ILD if the lung parenchymal abnormalities persist for a minimum of six months after the COVID infection has resolved. Post-COVID ILD should then be further subclassified based on distinct radiological patterns. In our retrospective cohort study, four patterns of post-COV...
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...
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...
Show MoreWe 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 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....
To the editor,
We thank N. Hürsoy and colleagues for their interest in our study of patients four months after severe COVID-19 [1]. We agree that there needs to be continued development of terms describing the radiographic appearance of post-COVID fibrotic-like patterns. We acknowledge that without the benefit of histopathology or serial imaging, our ability to define pulmonary fibrosis is limited.
The authors posit that parenchymal bands, irregular densities, and ground glass opacities, may be considered fibrotic-like patterns. We have included irregular densities, characterized as reticulations or traction bronchiectasis, as fibrotic-like changes. We did not include parenchymal bands [2], as these can be associated with atelectasis, which is common in COVID and can disappear over time [3]. Similarly, we did not include isolated ground glass opacities as fibrotic-like changes, as these have been found to decrease over time in CT lung cancer screening cohorts [4] and in other post COVID-19 cohorts [5, 6].
A priori, we evaluated for both previously established interstitial lung abnormality categories [7], as well as categories of radiographic abnormalities reported in Acute Respiratory Distress Syndrome (ARDS) survivors using an established scoring system [8]. This inclusive approach should facilitate meta-analyses and comparisons with future studies of COVID-19 survivors, interstitial lung disease studies, and studies of non-COVID ARDS survivors. Fu...
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