Dear Editor,

We read with great interest the recently published article in Thorax by Combes and colleagues titled “Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study” [1]. In this article, the authors present brief, post-hoc analyses of safety and efficacy data derived from the SUPERNOVA trial, a single-arm, multi-center, pilot study assessing the feasibility and safety of extracorporeal carbon dioxide removal (ECCO2R) to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress syndrome (ARDS) [2]. The study was conducted at 23 centers, each of which used one of three different ECCO2R devices.

We wish to communicate significant concerns regarding improper categorization of ECCO2R device performance as well as important study limitations impacting interpretation and value of the presented data. The differentiation between devices based on the terms “higher CO2 extraction” and “lower CO2 extraction” is incorrect based on supporting evidence and engineering principles summarized in this letter. In addition, safety data was presented and statistically compared without including available associated data that would bring in to question the implications of the analyses. As the manufacturer of one of the ECCO2R devices used in the SUPERNOVA pilot study, we are strong believers in the life-saving potential of ECCO2R technology and its role as a critical care lung support option. However, we also recognize the risks of ECCO2R therapy and the importance of providing users with all available safety data to enable accurate characterization of the risk profile. While we support the authors in publishing available safety data from this study, the data presented lacked critical information and represented key limitations that preclude the basis of the analysis as well as the stated conclusions.

The SUPERNOVA trial was not designed to investigate potential differences in device performance and safety, nor was such an analysis planned a priori [3]. However, in this post-hoc analysis, the data was reviewed retrospectively to compare differences in safety and efficacy between two groupings of the 3 devices, defined as either “higher CO2 extraction” or “lower CO2 extraction”. The question of “how much CO2 extraction is needed” to achieve certain therapeutic objectives is important, but the rationale used to categorize ECCO2R devices as “higher” versus “lower” extraction to address this question is fundamentally incorrect and, hence, undermines the entire analysis. In the SUPERNOVA study, CO2 extraction was not actually measured. It was assumed that CO2 extraction differences can be inferred based solely on differences in the operational blood flow rates and membrane surface area between devices.

The CO2 extraction rate of a given blood gas exchange device depends strongly on its unique gas transport efficiency [4,5]. In the device characterized as “low CO2 extraction” (the Hemolung RAS), gas transport efficiency is significantly increased by secondary flow patterns achieved through integration of a centrifugal pump within the fiber bundle to achieve higher CO2 extraction at lower flows with less membrane surface area and using smaller catheters. This is the defining design feature of the Hemolung device.
Data supporting similar CO2 extraction rates in ECCO2R devices operating at lower vs higher blood flows can be found in the literature. Hermann et al. published the results of a small study prospectively measuring CO2 extraction rates in 10 patients treated with ECCO2R using one of the devices also used in the SUPERNOVA trial that has been characterized as “higher CO2 extraction” [6]. With a membrane surface area of 1.3 m2, CO2 extraction rates of 70 mL/min (range of 42-85 mL/min), normalized to an inlet PCO2 of 45 mmHg, were measured at a blood flow of 1.0 L/min and a sweep gas flow of 14 L/min [7].

Barrett and colleagues recently published an in-vitro study characterizing CO2 extraction using the Hemolung RAS, which has a membrane surface area of 0.59 m2. CO2 extraction rates of 89 - 98 mL/min were measured at a blood flow of 0.4 L/min, a sweep gas flow of 10 L/min, and an inlet PCO2 of 45 mmHg [8]. The study followed ISO 7199:2016 standards for blood gas exchanger conformance testing and utilized three different CO2 extraction measurement methodologies.

This data from the literature indicates that use of the higher versus lower CO2 extraction nomenclature is not appropriate without validated measures of actual CO2 extraction. When comparing one ECCO2R device to another, higher blood flow and/or higher membrane surface area does not necessarily correlate with CO2 extraction. Thus, the conclusions drawn in the post-hoc analysis regarding differences in device CO2 extraction are incorrect.

So then, if not CO2 extraction, how can the observed differences between the two groups of devices be explained? Unlike the original publication of the SUPERNOVA results, this publication did not clearly reiterate the important limitations in the study design that can’t be ignored when trying to draw meaningful and scientifically sound conclusions from the data. As a pilot study conducted at 23 different sites in Europe and Canada, SUPERNOVA was not designed to generate standard-of-care or inter-device control data, thus post hoc analyses of data subsets are speculative. Many potential site-dependent differences or biases could exist in patient selection, cannulation techniques, anticoagulation management, ECCO2R management, and ventilation management. While many of these factors had constraints imposed by the protocol procedures, these procedures provided for enough variation in practice to open the door to bias impact. Thirty-three of the 95 patients enrolled were treated with the Hemolung device at five different centers with an enrollment variation of 1, 3, 7, 8, and 14 subjects. This variation alone is large enough to enable site-dependent differences just within subjects treated with the Hemolung device. One of the more notable limitations in the study design with respect to conducting between-device comparisons is that each site only used one of the three possible devices.

The post-hoc analysis also presented comparisons of safety data to support statistical differences in rates of hemolysis and bleeding between the two groupings of devices. These findings were of significant concern because they suggested higher rates than previously observed. Following publication of this article, we requested further information associated with the incidences of hemolysis presented in the analysis. Review of the additional information revealed several relevant observations with important implications for assessment of severity and device-relatedness. For example, of the seven hemolysis events reported with the Hemolung device, six were reported at a single site that treated only eight subjects which suggests possible biased reporting of hemolysis (or perhaps other unknown site-specific anomalies). Five of the seven incidents of hemolysis were reported to have occurred only on Day 0 of treatment, but there were no accompanying baseline measures taken prior to initiation of ECCO2R. The actual levels of plasma-free hemoglobin on which these five incidents of hemolysis were based was between 100 – 330 mg/L, which is an uncommonly low threshold for reporting of device-related hemolysis. The Extracorporeal Life Support Organization defines moderate hemolysis as peak plasma hemoglobin of 500-1000 mg/L occurring at least once during extracorporeal therapy and sustained for at least two consecutive days [8]. Given the severity of illness in the underlying patient population, it cannot be ruled out that the low levels of plasma-free hemoglobin reported to have occurred on Day 0 weren’t present at baseline, making it difficult to determine device-relatedness. Furthermore, the use of simple bivariate comparisons in a post-hoc analysis cannot ignore Type 1 error inflation where the likelihood of observing a statistically significant p-value increases with the number of comparisons made. In short, the safety data presented is not controlled, is without baseline comparisons, reflects a reasonable likelihood of bias, and does not reflect a priori Type 1 error control for analysis.

Additionally, the safety data was presented without any relevant details that would enable readers to effectively weigh the risks of ECCO2R against the risks of ventilator-associated lung injury. What impact did these events have on the patient? What medical interventions were required? How did the events impact ECCO2R therapy or ventilation status? Was ICU length of stay impacted? Without this perspective and without control data, the information presented could be misinterpreted or misused. The communication concludes with the statement, “Future randomised clinical trials assessing the overall benefit and harm of ultraprotective ventilation should be carried out with ECCO2R devices equipped with a larger membrane lung and blood flows between 800 and 1000 mL/min.” Given the many limitations of this post-hoc analysis, the incorrect differentiation in CO2 extraction between devices, and the paucity of information provided with the safety data, this conclusion is not supported.

Respectfully,

Laura W. Lund, Ph.D. Jeremy D. Kimmel, Ph.D.
Vice President of Clinical Science Vice President of New Technology
ALung Technologies, Inc. ALung Technologies, Inc.

Section Bibliography

1. Combes A, Tonetti T, Fanelli V et al. Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study. Thorax 2019; 74: 1179-1181
2. Combes A, Fanelli V, Pham T, Ranieri VM. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Medicine 2019; 45: 592-600
3. Fanelli V, Ranieri MV, Mancebo J et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Critical Care 2016; 20: 1-7
4. AAMI Standards and Recommended Practices. Association for the Advancement of Medical Instrumentation. Cardiovascular implants and artificial organs — Blood-gas exchangers (oxygenators). ANSI/AAMI/ISO 7199:2009/(R)2014 and ANSI/AAMI/ISO 7199:2009/A1:2012(R)2014.
5. Hattler B, and Federspiel W: Chapter 6: Gas exchange in the venous system: Support for the failing lung. In: The artificial lung. Edited by Vaslef S, Anderson R. Georgetown, TX: Landes Bioscience; 2002: 133–174.

It was with great interest and not a little concern that we read the recent Brief Communication by Janson and colleagues [1] into the impact of pressurised metered dose inhalers (pMDIs) on the global warming potential (GWP) of respiratory care. We note the tenacity of one of the authors who has succeeded in publishing a second paper [2] based on a similar, flawed logic just two weeks later. The sense of proportion that is missing in both reports has, thankfully, been identified in the press this week.[3] However, we feel it essential to scrutinise the current contribution scientifically.

The authors report the carbon footprints of a range of devices marketed by GlaxoSmithKline (GSK) following analysis undertaken by the Carbon Trust (a UK not-for dividend company). Subsequently, calculations were undertaken aimed to determine how the carbon footprint of inhalation therapy in the UK’s National Health Service (NHS) might be reduced by altering the prescribing patterns of UK physicians (where more pMDIs are prescribed than dry powder inhalers (DPIs)) to resemble those of Swedish physicians (where the converse holds). While we acknowledge the authors’ declaration that their data are potentially flawed by the fact that their calculations are based on extrapolating the carbon footprints of just three device formats manufactured by one company to predict the effects of total DPI and pMDI usage in the UK when the carbon footprints of most other devices are unknown, we would suggest that this is not the only potential weakness of the analysis. It is also erroneous to compare the UK to Sweden by looking solely at prescribing data for England, and not the entire UK. The modelling of GSK-GSK product switches ignored that there may be both lower GWP and lower cost alternative DPIs or inhalation device formats. Indeed, we are deeply concerned the reports by such respected authors could be interpreted as promoting a commercial bias of one company recommending switching patients to their own – frequently more expensive – products to save the planet, where there could be both lower carbon footprint and lower cost from alternatives.

This is the second occasion that we have felt obliged to respond to such analysis and invite scientists and clinicians to clamour for independent assessment of the multiple ramifications of developing medicine that is both effective and environmentally sustainable.[4] An additional incorrect assumption perpetuated in this second article, that has direct clinical consequences for respiratory disease patients, is that all patients can be summarily switched from pMDIs to DPI therapy irrespective of their age, the nature and severity of their obstructive airway disease, or ability to use DPIs efficiently. We would remind readers that healthcare professionals must consider many therapeutic factors when selecting the most appropriate inhaler device for individual patients if they wish treatment to be effective. For example, DPIs, are seldom appropriate for use in young children, the elderly and infirm and those with considerable, irreversible airways obstruction.[5] The authors’ data does not differentiate between asthma and COPD prescriptions. Several clinical modelling assumptions in the current Brief Communication are therefore unrealistic and undermine the data in their article. Of significant concern is their calculation based on 2 doses of short-acting beta agonist (SABA) a day. If these are asthma patients, then the pMDI-DPI switch is poor practice and the prescribing signifies uncontrolled asthma (likely because regular inhaled corticosteroids (ICS) are not being taken, or device use is incorrect), and it further indicates the need for an urgent healthcare professional review to reassess medication, inhaler device, inhaler technique, adherence and patient motivation.[6, 7]

We agree wholeheartedly with the authors that it is necessary to take an environmentally sustainable approach to prescribing. However we have grave reservations about the assertion that switching patients’ from pMDIs to the cheapest DPIs would result in large carbon savings, while ignoring the carbon impact during manufacture of devices (not included in their limited modelling), and possible consequences for loss of disease control and consequent morbidity and mortality from obstructive airways diseases such as asthma.

We note that the authors only report the carbon footprint of several of GSK’s product range, rather than undertaking an holistic lifecycle analysis of the products.[8] Such an analysis was performed by Jeswani and Azapagic for pMDIs made with the propellants HFA134, HFA227, HFA152 and a GSK DPI-Diskus device.[9] Although the DPI outperformed the HFA134 and HFA227 pMDIs for GWP; human toxicity, marine eutrophication and fossil depletion were all concluded to be worse for DPI-Diskus than HFA-based pMDIs. In fact, the full spectrum of long-term environmental effects of DPI-Diskus were actually worse for eight out of fourteen environmental impact metrics than for pMDIs. The inhaled pharmaceutical development sector is currently examining the switchover of HFA134 and HFA227 to a low GWP alternative propellant HFA152a. Once the HFA152a switchover has been made, pMDIs will have an equivalent carbon footprint to DPIs, but have improved environmental impact profile.[9] Switchover may also present an opportunity to reduce the extent of manufacturing overfill (many “200 dose” inhalers are currently filled to between 220-240 dosages to ensure through-life stability) which would also have an impact on GWP.

When undertaking their analysis of the potential reductions in carbon emissions for individual patients and for the NHS if a pMDI-DPI switch were enacted, the authors used data from the Carbon Footprint Certification Summary Report for several GSK inhalation products [10] included in their supplementary material. While we recognise and acknowledge the invaluable and sector-leading work of the Carbon Trust, we note the authors of the current study have not facilitated close scrutiny of the primary carbon calculation methodologies, in contrast to other studies in the scientific literature (e.g. [9, 11]). Indeed, we note one of the Carbon Footprint Report’s 'Recommended Further Actions' was to: “collect accurate, recent primary data”.[10] Since we have no access to them, it is impossible for the reader to know how old and complete the data are that were presented to the Carbon Trust. Given this shortcoming, we believe it is at best unjustified, and at worst thoroughly inappropriate to predict the GWP reduction for inhalation therapy by assuming that all pMDI products on the market have the same carbon footprint as GSK’s Evohaler (20 kg CO2e), and that all prescribed DPIs possess the same GWP as the Ellipta and Diskus devices of ~1kg CO2e per device. This is patently untrue in the case of the Salamol salbutamol pMDI, for example, which has a carbon footprint which is approximately half that modelled in the current communication.[8, 11] All DPIs have widely different structures and contents in terms of parts and plastics involved in their manufacture, or the number of dose units contained in the device. As a significant contributor to GWP in DPIs is the active pharmaceutical ingredient (API),[11] it follows that the move from mono-therapy towards double and triple combinations is therefore more likely to be a move for DPIs towards higher GWP.

The authors’ comparisons between the percentage of patients prescribed pMDIs in the UK (70%) compared to Sweden (10%) extends no further than the pharmacological category of prescribed inhaler numbers in England; and does not take into account the prescribed brand (and its corresponding carbon footprint), nor the indication for the prescribed therapy. Such an assessment is a blunt tool and fails to account for potential differences in disease care pathways in each country. For example, NICE [12] and SIGN/BTS [7] guidelines advocate the use of SABA use as first line therapy for asthma, and as pMDIs are cheapest, this may account for the high levels of prescribing in England compared to other countries. There is no assessment as to whether the SABAs prescribed in Sweden are identical to those in the UK. The exercise of replicating the Swedish prescribing patterns in the UK context is undertaken with no regard to the disease(s) being treated in which (sub)-populations of patients. The authors summarily assert that that the reasons underpinning the different prescribing patterns “could be related to marketing strategies and prescribers’ and patients’ biases”. This is a remarkable conclusion from authors representing one of the world’s leading producers of inhalation medicines regarding the prescribing of their own products. Indeed, we note that the economic cost to the NHS of the switches recommended in this article would be substantial, given the higher cost of many of GSK’s DPIs compared with pMDI. [2]

We have pointed out that Janson and colleagues have assumed in their analysis that all patients in the UK can be switched from pMDI to DPI therapy regardless of fact that not all patients can use DPIs effectively (because of their age, and/or the nature or severity of their disease) and the influence of their own satisfaction with – or preference for – the switched device which is a known factor influencing therapeutic outcome.[13] In contrast to DPIs, all patients with sufficient hand motor function can use pMDIs effectively in combination with a spacer device, when well-instructed. Indeed, the pMDI combination compounds of salmeterol xinafoate with fluticasone propionate, marketed by this company, have been shown to be more effective in real life studies on improving asthma control [14] and COPD [15] disease exacerbations than the very same combination given as a DPI.

In light of the potential for loss of disease control when switching devices, it seems imperative that the carbon footprint of potential loss of disease control also be presented to healthcare professionals alongside the carbon footprint implications of the switchover itself. [16, 17] There is no assessment of the carbon footprint of the clinical visits involved in switching and re-training patients. Disease destabilisation and the associated “carbon cost” of unnecessary emergency and secondary care disease management would also be significant. For example, Goulet et al. [11] estimated that the carbon footprint of a single bronchodilator dose administered with an electric nebuliser is a considerable 0.0294-0.0477 kg CO2e, while Moorfields Eye Hospital estimated that the carbon footprint of a single patient visit was between 8-10 kg CO2e per patient, per visit. [18] Therefore, the carbon reductions described by the authors may not reflect the full costs of the switchover. We advocate face-to-face training and assessment of optimal inhaler technique to ensure patients are prescribed an inhaler device that they are able to use in order to manage their asthma or COPD, before examining the carbon footprint of a patient’s inhalation therapy as the secondary prescribing assessment.

Our final substantive objection to the approach taken by the authors in this manuscript is the comparison of the carbon footprint of a patient’s inhalation therapy to reductions achievable by lifestyle choices, such as changing from a meat-based to plant-based diet, changing transport modalities or how clothes are washed. Patients with lung disease or any other disease do not choose to have their condition, nor is it a lifestyle choice to use therapy with which best manages the condition for each individual. The flippant comparisons made in the recent report [2] resulted in newspaper headlines that potentially add to the burden of anxiety of patients by amplifying the “guilt” of contributing to climate change when taking an essential medicine. There is a need for balanced, articulate and, most importantly, accurate analysis that avoids the stigmatisation of patients with asthma and COPD through news headlines that do not address the nuances of planning the reduction of healthcare impact on climate change.

We are all concerned about the environmental impact of human activity on global warming and the environment. [19] Several of us are engaged in research to accelerate the introduction of low GWP therapies into the clinic, or improve our management of lung disease through appropriate device utilization. However, this communication lacks balance in its discussion, while potentially pressurizing healthcare professionals and patients inappropriately to stop or switch successful therapeutic plans. There are undoubtedly opportunities to consider the “greenest” product when patients commence therapy or alter it for reasons of poor disease control or inadequate inhaler technique.

‘Greening’ healthcare requires a more holistic assessment of the impact of inhaler choice on wider environmental metrics, as well as the consequences of possible destabilisation of patients’ conditions, and the carbon-intensiveness of the consequent extra emergency and follow-up care. While the authors correctly state that: “Key considerations for inhaler selection include healthcare professional knowledge of all the devices; inhalation manoeuvre achieved; airway disease severity, patient’s ability to use their device correctly and their personal preferences” we feel that publications such as the current report have potential to create carbon targets for prescribing in isolation from such nuanced considerations. Healthcare practitioners will welcome evidence-based approaches for identifying suitable patients and strategies for switching devices. If the burden of reducing the GWP of healthcare in the NHS is to be placed on respiratory physicians, it is essential that they have access to prescribing tools that allow appropriate stratification of product choices for patients to manage their therapeutic carbon footprint. There is no one-size-fits-all approach in respiratory care, and we believe the current Brief Communication contributes little to our ability to deliver the changes necessary to manage the environmental impact of inhalation therapies.

References
1. Janson C, Henderson R, Löfdahl M, Hedberg M, Sharma R, Wilkinson AJK. Carbon footprint impact of the choice of inhalers for asthma and COPD. Published Online First: 07 November 2019. doi: 10.1136/thoraxjnl-2019-213744
2. Wilkinson AJK, Braggins R, Steinbach I, Smith J. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019;9(10).
3. Ingraham C. No, asthma inhalers are not ‘choking the planet’. Washington Post. 2019 11 Nov 2019 https://www.washingtonpost.com/business/2019/11/11/no-asthma-inhalers-ar....
4. Levy M, Murnane D, Barnes PJ, Sanders M, Fleming L, Scullion J, et al. Inhaler devices and global warming: Flawed arguments - A Response to Wilkinson et al. Costs of switching to low global warming potential inhalers. An economic and carbon footprint analysis of NHS prescription data in England. BMJ Open. 2019. Available from: https://bmjopen.bmj.com/content/9/10/e028763.responses#inhaler-devices-a....
5. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. European Respiratory Journal. 2002;19(2):246-51.
6. Global Initiative for Asthma (GINA). The Global Strategy for Asthma Management and Prevention 2019. Available from: http://www.ginasthma.org.
7. Scottish Intercollegiate Guideline Network (SIGN), The British Thoracic Society British guideline on the management of asthma 2019. Available from: https://www.sign.ac.uk/sign-158-british-guideline-on-the-management-of-a...
8. Jolliet O, Margni M, Charles R, Humbert S, Payet J, Rebitzer G, et al. IMPACT 2002+: A new life cycle impact assessment methodology. International Journal of Life Cycle Assessment. 2003;8(6):324.
9. Jeswani HK, Azapagic A. Life cycle environmental impacts of inhalers. Journal of Cleaner Production. 2019;237.
10. Trust C. Carbon Trust. GlaxoSmithKline PLC. Product Carbon Footprint Certification Summary Report 2017 (Supplementary Material to Janson et al. Thorax, 2019). Available from: https://thorax.bmj.com/content/thoraxjnl/early/2019/11/07/thoraxjnl-2019....
11. Goulet B, Olson L, Mayer BK. A comparative life cycle assessment between a metered dose inhaler and electric nebulizer. Sustainability (Switzerland). 2017;9(10).
12. National Institute for Health and Care Excellence (NICE). Asthma: diagnosis, monitoring and chronic asthma management. NICE guideline [NG80]. 2017. Available from: https://www.nice.org.uk/guidance/ng80
13. Plaza V, Giner J, Calle M, Rytilä P, Campo C, Ribó P, et al. Impact of patient satisfaction with his or her inhaler on adherence and asthma control. Allergy and Asthma Proceedings. 2018;39(6):437-44.
14. Price D, Roche N, Christian Virchow J, Burden A, Ali M, Chisholm A, et al. Device type and real-world effectiveness of asthma combination therapy: An observational study. Respiratory Medicine. 2011;105(10):1457-66.
15. Jones R, Martin J, Thomas V, Skinner D, Marshall J, d’Alcontres MS, et al. The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: A UK database study. International Journal of COPD. 2017;12:2445-54.
16. Björnsdõttir US, Gizurarson S, Sabale U. Potential negative consequences of non-consented switch of inhaled medications and devices in asthma patients. International Journal of Clinical Practice. 2013;67(9):904-10.
17. Melani AS, Paleari D. Maintaining control of chronic obstructive airway disease: Adherence to inhaled therapy and risks and benefits of switching devices. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2016;13(2):241-50.
18. Moorfields Hospital Foundation Trust. Sustainable Development Management Plan 2017 – Page 9. Available from: https://www.moorfields.nhs.uk/sites/default/files/Item%2009%20Sustainabl...
19. Usmani OS, Scullion J, Keeley D. Our planet or our patients—is the sky the limit for inhaler choice? The Lancet Respiratory Medicine. 2019;7(1):11-3.

To The Editor and to The Authors.

I wish to congratulate the authors. I find their review on RSV-induced severe disease attractive in all respects. It impressively presents research ranging from epidemiology to molecular immunology, and includes promising treatment opportunities. My perhaps peripheral comments relate to the authors’ conclusion that “much remains to be discovered regarding the host response to RSV infection”.

Loss of epithelial cells and pathogenic roles of exaggerated epithelial regeneration.
I’d like to dwell somewhat on RSV-induced epithelial cell loss, which is mentioned in passing in the review. Bodies constituted of many epithelial cells clumped together in airway lumen material have been named Creola bodies by Naylor (1) who demonstrated numerous Creola bodies in association with exacerbations of asthma. However, Creola bodies, as a sign of widespread patches of epithelial shedding, may also be a prominent feature of RSV infection. Indeed, in RSV-infected infants Creola bodies in aspirates seem to be a requisite for the infection to be followed by development of asthma (2,3). This is of interest because epithelial regeneration processes alone, rather than the reputed increased permeability to inhaled material (which is not observed in vivo in asthma (4)) are causative regarding several facets of airway inflammation and remodelling (5,6).

Lethal RSV infections in children are associated with extensive and patchy loss of bronchial epithelial cells as well as occurrence of a fibrinous exudate (7) that characterizes sites of epithelial regeneration (4). Exaggerated epithelial regeneration could thus qualify as a multipotent pathogenic factor in RSV-induced diseases beyond asthma. I think it would be of interest to learn about occurrence of Creola bodies and exaggerated epithelial regeneration in association with RSV infection-induced severe disease from infancy to old age.

Antimicrobial peptides and plasma exudation as first line airway defence.
The authors have included a small § on airway innate immunity aspects that could reduce or avert infections following RSV exposure. The authors specifically mention that cathelicidin, an antimicrobial peptide (AMP), could prevent RSV invasion. In accord with most features of innate immunity, local cells, which are readily studied in vitro, are generally considered sole producers of AMPs. However, in vivo in patients the situation is different. In a rare study, where the in vivo origin of induced airway surface cathelicidin was demonstrated, this AMP appeared on the airway surface exclusively as a component of plasma exudation (8). This information probably needs to be complemented with further in vivo observations in guinea-pig and human airways demonstrating that induced plasma exudation responses (eg by topical histamine challenges) produce brief and localised microvascular-epithelial exudation of non-sieved plasma. This response occurs without producing mucosal oedema, without harming the epithelium, and without increasing epithelial perviousness in the opposite direction (4).

The non-sieved and non-injurious nature of airways plasma exudation is important because cathelicidin would be accompanied by all antimicrobial proteins/peptides contained in circulating plasma (4). Also, even if AMPs occur as a result of plasma exudation, rather than being secreted by local cells, this remains a first line innate defence operating on the surface of an intact epithelial lining.

It is another matter if RSV invasion has occurred and epithelial loss is extensive – Then plasma exudation also occurs but is much more intense and of much longer duration (4). The latter response is needed to provide a suitable milieu for prompt and speedy epithelial regeneration, but if too exaggerated the effect may be detrimental to the host (4).

Carl Persson
carl.persson@med.lu.se
Laboratory Medicine
University Hospital of Lund
Lund, Sweden

1. Naylor B. The shedding of the mucosa of the bronchial tree in asthma. Thorax 1962; 17:69-72.
2. Yamada Y, Yoshihara S, Arisaka O. Creola bodies in wheezing infants predict the development of asthma. Pediatr Allergy Immunol 2004; 15:159-62.
3. Yamada Y, Yoshihara S. Creola bodies in infancy with respiratory syncytial virus bronchiolitis predict the development of asthma. Allergol Int 2010; 59:375-80.
4. Persson C. Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma. J Allergy Clin Immunol 2019; 143:1271-86.
5. Persson CG, Erjefalt JS, Erjefalt I, Korsgren MC, Nilsson MC, Sundler F. Epithelial shedding--restitution as a causative process in airway inflammation. Clin Exp Allergy 1996; 26:746-55.
6. Erjefalt JS, Persson CG. Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 1997; 52:1010-2.
7. Johnson JE, Gonzales RA, Olson SJ, Wright PF, Graham BS. The histopathology of fatal untreated human respiratory syncytial virus infection. Mod Pathol 2007; 20:108-19.
8. 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; 42:383-91.