We have read with interest the letter from Dr. Eisenhut in this issue of the Journal and thank him for his comments on our work. The theory regarding reduced Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction in acute respiratory distress syndrome (ARDS) is interesting, though remains speculative at present. While some rationale exists to explain why transmembrane ion channels may be dysregulated in inflammation,1 we did not directly examine CFTR function in our original work.2 To test this hypothesis, direct augmentation of CFTR function during a nasal potential difference reading, or measurement of sweat chloride concentration, or another surrogate measure of CFTR function, would need to additionally be incorporated into our study design. We are not aware of any published studies of directly measured CFTR function in adults with ARDS.
References
1. Eisenhut M, Wallace H. Ion channels in inflammation. Pflugers Arch 2011; 461(4): 401-21.
2. MacSweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome. Thorax 2021; 76(11): 1099-107.
3. Davis PB, Del Rio S, Muntz JA, Dieckman L. Sweat chloride concentration in adults with pulmonary diseases. Am Rev Respir Dis 1983; 128(1): 34-7.
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
It is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (...
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
It is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel by reducing its average open probability and channel expression at the cell surface (3).
I therefore propose that the findings of MacSweeney et al. are due to a reduced CFTR function caused by the cytokine storm found in ARDS (4). We found unequivocal and reproducible evidence of a reduced CFTR function in patients with septicaemia induced pulmonary edema as reflected in significantly elevated sweat chloride levels in patient with pulmonary edema compared to controls with the same infection but no lung injury and compared to those without any infection (2). One patient we previously reported had a temporarily elevated sweat chloride level consistent with cystic fibrosis indicating as severe and transient impairment of systemic CFTR function (5). The reduced CFTR function results then in increased ENaC function found by the investigators and also found in patients with cystic fibrosis where this results from a wide range of causes of CFTR dysfunction (6).
References:
1. Mac Sweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome.Thorax 2021;76:1099-1107.
2. Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW.Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.Pediatr Crit Care Med. 2006 Mar;7(2):119-24.
3. Rauh R, Hoerner C, Korbmacher C. δβγ-ENaC is inhibited by CFTR but stimulated by cAMP in Xenopus laevis oocytes. Am J Physiol Lung Cell Mol Physiol. 2017 Feb 1;312(2):L277-L287. doi: 10.1152/ajplung.00375.2016. Epub 2016 Dec 9. PMID: 27941075.
4. Eisenhut M Wallace H.Ion channels in inflammation.Pflugers Arch. 2011 Apr;461(4):401-21.
5. Eisenhut M, Southern KW.Positive sweat test following meningococcal septicaemia.Acta Paediatr. 2002;91(3):361-2.
6. Taylor CJ, Hardcastle J, Southern KW. Physiological measurements confirming the diagnosis of cystic fibrosis: the sweat test and measurements of transepithelial potential difference. Paediatr Respir Rev 2009 Dec;10(4):220-6.
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached and begins to decrease. For patients with DMD, this decline occurs around 13.5 (range-9-17) years of age.6 At this point, cough flows tend to drastically decrease, increasing the risk of pneumonia, but can be improved with air stacking.2,3 Therefore, it is our opinion that air stacking is not a burden but when to initiate is arguable.
References
1. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):222-227.
2. Bach JR, Kang SW. Disorders of ventilation: weakness, stiffness, and mobilization. Chest 2000; 117(2):301-303.
3. Kang SW, Bach JR. Maximum insufflation capacity: vital capacity and cough flows in neuromuscular disease. Am J Phys Med Rehabil 2000;79(3):
4. Rideau Y, Bach J. Efficacité therapeutique dans la dystrophie musculaire de Duchenne. J Readapt Med 1982;2(3):96-100.
5. Deo P, Bach JR. Noninvasive ventilatory support to reverse weight loss in Duchenne muscular dystrophy: a case series. Pulmonol 2019;25(2):79-82.
6. Bach J, Alba A, Lee M, Rideau Y. Long-term respiratory rehabilitation in the treatment of neuromuscular disease. Ann Readapt Med Phys 1983;26:101-109.
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
We appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of LVR during exacerbations and in individuals with lower pulmonary function, the optimal timing for routine LVR therapy was not identified in our study of younger individuals with preserved lung function. While it would be ideal to conduct a randomized trial of LVR therapy in individuals with DMD beginning at the apex of their vital capacity trajectory,[9] a lengthy and costly study would be needed to evaluate changes over several years in order to determine the benefits of LVR. In contrast, such a study is not needed in individuals with advanced disease, in whom there is sufficient evidence to justify regular treatment. Given that uptake of routine LVR therapy for individuals with neuromuscular disease is not uniform, additional evidence is still needed to guide best practices for clinical care. Further exploration is required to ensure that LVR is introduced when it will be of benefit to individuals with neuromuscular disease.
References
1. Birnkrant DJ, Bushby KM, Amin RS, et al. The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatric Pulmonology 2010;45(8):739-48.
2. Amin RM, I; Zielinski,D; Adderley,R; Carnevale,F; Chiang,J; Cote,A; Daniels,C; Daigneault,P; Harrison.C; Katz,S; Keilty,K; Majaesic,C; Moraes.T.J; Price,A; Radhakrishnan,D; Rapoport,A; Spier,S; Thavagnanam,S; Witmans,M; Canadian Thoracic Society. Pediatric home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline executive summary. Canadian Journal of Respiratory, Critical Care and Sleep Medicine 2017;1(1):7-36.
3. Hull J, Aniapravan R, Chan E, et al. British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. Thorax 2012;67 Suppl 1:i1-40.
4. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170(4):456-65.
5. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol 2018;17(4):347-61. doi: 10.1016/s1474-4422(18)30025-5 [published Online First: 2018/02/06]
6. Birnkrant DJ. The American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Pediatrics 2009;123 Suppl 4:S242-S44.
7. McKim DA, Katz SL, Barrowman N, et al. Lung Volume Recruitment Slows Pulmonary Function Decline in Duchenne Muscular Dystrophy. Archives of Physical Medicine and Rehabilitation 2012;93(7):1117-22.
8. Katz SL, Barrowman N, Monsour A, et al. Long-Term Effects of Lung Volume Recruitment on Maximal Inspiratory Capacity and Vital Capacity in Duchenne Muscular Dystrophy. Ann Am Thorac Soc 2016;13(2):217-22.
9. Chiou M, Bach JR, Jethani L, et al. Active lung volume recruitment to preserve vital capacity in Duchenne muscular dystrophy. J Rehabil Med 2017;49(1):49-53. doi: 10.2340/16501977-2144 [published Online First: 2016/09/16]
10. McDonald CM, Gordish-Dressman H, Henricson EK, et al. Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids. Neuromuscul Disord 2018;28(11):897-909. doi: 10.1016/j.nmd.2018.07.004 [published Online First: 2018/10/20]
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 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.
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.
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 have read with interest the letter from Dr. Eisenhut in this issue of the Journal and thank him for his comments on our work. The theory regarding reduced Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction in acute respiratory distress syndrome (ARDS) is interesting, though remains speculative at present. While some rationale exists to explain why transmembrane ion channels may be dysregulated in inflammation,1 we did not directly examine CFTR function in our original work.2 To test this hypothesis, direct augmentation of CFTR function during a nasal potential difference reading, or measurement of sweat chloride concentration, or another surrogate measure of CFTR function, would need to additionally be incorporated into our study design. We are not aware of any published studies of directly measured CFTR function in adults with ARDS.
References
1. Eisenhut M, Wallace H. Ion channels in inflammation. Pflugers Arch 2011; 461(4): 401-21.
2. MacSweeney R, Reddy K, Davies JC, et al. Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome. Thorax 2021; 76(11): 1099-107.
3. Davis PB, Del Rio S, Muntz JA, Dieckman L. Sweat chloride concentration in adults with pulmonary diseases. Am Rev Respir Dis 1983; 128(1): 34-7.
MacSweeney et al. in their recent report of transepithelial nasal potential difference measurements in patients at risk of acute respiratory distress syndrome documented that the amiloride response of nasal respiratory epithelium was significantly greater in patients who progressed to develop ARDS compared to those who did not (1). It was also greater in patients who died with ARDS compared to survivors. This is consistent with an increased epithelial sodium channel function in patients at risk of ARDS and its associated mortality. We previously conducted nasal potential difference measurements in children with and without meningococcal septicemia associated pulmonary edema and controls on a Pediatric Intensive Care Unit (2). We found that the amiloride response was greater in patients with pulmonary edema compared to controls but this effect did not reach statistical significance which may have been due to the small number of patients we could enrol (n=4 with pulmonary edema, n=2 with septicemia without pulmonary edema and 8 controls) (2). Despite this small number of patients we found that the nasal potential response to a low chloride solution in patients with septicemia associated pulmonary edema compared to controls was significantly reduced indicating a concomitant dysfunction of respiratory epithelial chloride channels.
Show MoreIt is known from in vitro studies that the epithelial sodium channel is inhibited by the Cystic Fibrosis Transmembrane Conductance Regulator (...
We thank the authors for their contribution of a RCT of boys with DMD (FVC>60%) with the intervention of active LVR (air stacking) twice daily for two years. In our clinical practice, we have introduced LVR to thousands of patients with ventilatory pump failure and over 300 with DMD. Although we have not found LVR to preserve or improve vital capacity (VC), patients with 0 mL of VC can survive for decades using up to continuous noninvasive ventilatory support (CNVS). On the other hand, improvement of maximum insufflation capacity (MIC) is reported to improve significantly with practice of LVR, although this is also not crucial.1 What is certain is that tachypneic hypercapnic patients with shallow breathing associated with supplemental oxygen therapy often cannot normalize their blood gases by NVS settings until the O2 is discontinued and the patient practices LVR aggressively for several weeks to several months. At that point their lungs become more compliant and delivered air volumes can normalize their blood gases.2,3 Also, ventilator “unweanable” patients who practice air stacking via mouth and/or nose pieces are much easier to extubate to mouthpiece and nasal CNVS than patients who have not practiced this technique.3,4 Further, air stacking can improve peak cough flows (PCF), phonation, and time to swallow food.5 While McKim et al. suggested initiation of air stacking for DMD once VC decreases below 80%, we have usually begun once the absolute plateau VC is reached...
Show MoreWe appreciate Dr. Ganapa and colleagues’ letter in response to our randomized controlled trial of lung volume recruitment (LVR) in Duchenne muscular dystrophy (DMD). We wholeheartedly agree that LVR has a critical role in the management of individuals with DMD during acute exacerbations and in individuals with advanced neuromuscular disease, especially in those with respiratory failure. The use of LVR in this context is supported by international clinical care guidelines [1-6] and data which demonstrates improvement in lung function decline and maximum insufflation capacity with routine twice-daily LVR.[7-9]
In our cohort with relatively preserved lung function (baseline median FVC 84.8%, IQR 73.3, 95.5%), the median age of our group (baseline median 11.5 years, IQR 9.5, 13.5 years) is slightly younger than that described by Dr. Ganapa, in whom routine LVR is initiated. Recent data from the Cooperative International Neuromuscular Research Group’s Duchenne Natural History Study indicates, however, that peak median FVC occurs at age 17.0-17.9 years in those with glucocorticoid exposure for greater than one year, compared to age 12.0-12.9 years in those not treated with glucocorticoids.[10] Eighty-nine percent of our cohort were treated with systemic steroids, which likely explains why many had normal FVC at baseline and why it was challenging to show improvements in the rate of decline of FVC over two years with LVR treatment.
Despite the clear benefits of L...
Show MoreThank 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 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 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....
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).
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...
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