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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 bron...
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).
University Hospital of Lund
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.