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Published in: Respiratory Research 1/2022

Open Access 01-12-2022 | Expectoration | Research

Bronchial eosinophils, neutrophils, and CD8 + T cells influence asthma control and lung function in schoolchildren and adolescents with severe treatment-resistant asthma

Authors: Miriam Cardoso Neves Eller, Karina Pierantozzi Vergani, Beatriz Mangueira Saraiva-Romanholo, Natália de Souza Xavier Costa, Jôse Mára de Brito, Leila Antonangelo, Caroline Silvério Faria, Joaquim Carlos Rodrigues, Thais Mauad

Published in: Respiratory Research | Issue 1/2022

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Abstract

Background

Studies in adult severe treatment-resistant asthma (STRA) have demonstrated heterogeneous pathophysiology. Studies in the pediatric age group are still scarce, and few include bronchial tissue analysis.

Objective

We investigated 6–18-year-old patients diagnosed with STRA in Sao Paulo, Brazil, by characterizing the different lung compartments and their correlations with asthma control and lung function.

Methods

Inflammatory profiles of 13 patients with a confirmed diagnosis of STRA were analyzed using blood, induced sputum, bronchoalveolar lavage, viral and bacterial screens and endobronchial biopsy. Inflammatory cells, cytokines, and basement membrane thickening were tested for correlations with the asthma control test (ACT) and spirometry and plethysmography parameters.

Results

Endobronchial biopsy specimens from 11 patients were viable for analysis. All biopsies showed eosinophilic infiltration. Submucosal (SM) eosinophils and neutrophils were correlated with worse lung function (pre-BD FEV1), and SM neutrophils were correlated with fixed obstruction (post-BD FEV1). Intraepithelial (IE) neutrophils were positively correlated with lung function (pre-BD sGaw). CD8 + T cells had the highest density in the IE and SM layers and were positively correlated with ACT and negatively correlated with the cytokines IL1β, IL2, IL5, IL7, IL10, IL12, IL17, GCSF, MCP-1, INF-δ, and TNFα in sputum supernatant. The ASM chymase + mast cell density correlated positively with quality-of-life score (pAQLQ) and ACT.

Conclusion

Eosinophils and SM neutrophils correlated with worse lung function, while IE neutrophils correlated with better lung function. Most importantly, CD8 + T cells were abundant in bronchial biopsies of STRA patients and showed protective associations, as did chymase + mast cells.
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Literature
1.
go back to reference Cook J, et al. Managing the pediatric patient with refractory asthma: a multidisciplinary approach. J Asthma Allergy. 2017;10:123–30.CrossRef Cook J, et al. Managing the pediatric patient with refractory asthma: a multidisciplinary approach. J Asthma Allergy. 2017;10:123–30.CrossRef
2.
go back to reference Fleming L, Heaney L. Severe asthma-perspectives from adult and pediatric pulmonology. Front Pediatr. 2019;7:389.CrossRef Fleming L, Heaney L. Severe asthma-perspectives from adult and pediatric pulmonology. Front Pediatr. 2019;7:389.CrossRef
3.
go back to reference Louis R. Severe asthma: how can we differentiate phenotypes? Swiss Med Wkly. 2009;139(192):274. Louis R. Severe asthma: how can we differentiate phenotypes? Swiss Med Wkly. 2009;139(192):274.
4.
go back to reference Martin Alonso A, Saglani S. Mechanisms mediating pediatric severe asthma and potential novel therapies. Front Pediatr. 2017;5:154.CrossRef Martin Alonso A, Saglani S. Mechanisms mediating pediatric severe asthma and potential novel therapies. Front Pediatr. 2017;5:154.CrossRef
5.
go back to reference Mthembu N, et al. Respiratory viral and bacterial factors that influence early childhood asthma. Front Allergy. 2021;2:692841.CrossRef Mthembu N, et al. Respiratory viral and bacterial factors that influence early childhood asthma. Front Allergy. 2021;2:692841.CrossRef
6.
go back to reference SabogalPiñeros YS, et al. Eosinophils capture viruses, a capacity that is defective in asthma. Allergy. 2019;74(10):1898–909.CrossRef SabogalPiñeros YS, et al. Eosinophils capture viruses, a capacity that is defective in asthma. Allergy. 2019;74(10):1898–909.CrossRef
7.
go back to reference Bossley CJ, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129(4):974–82.CrossRef Bossley CJ, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J Allergy Clin Immunol. 2012;129(4):974–82.CrossRef
8.
go back to reference Ciepiela O, Ostafin M, Demkow U. Neutrophils in asthma–a review. Respir Physiol Neurobiol. 2015;209:13–6.CrossRef Ciepiela O, Ostafin M, Demkow U. Neutrophils in asthma–a review. Respir Physiol Neurobiol. 2015;209:13–6.CrossRef
9.
go back to reference Davis KU, Sheats MK. The role of neutrophils in the pathophysiology of asthma in humans and horses. Inflammation. 2021;44(2):450–65.CrossRef Davis KU, Sheats MK. The role of neutrophils in the pathophysiology of asthma in humans and horses. Inflammation. 2021;44(2):450–65.CrossRef
10.
go back to reference Andersson CK, et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J Allergy Clin Immunol. 2017;139(6):1819–29.CrossRef Andersson CK, et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J Allergy Clin Immunol. 2017;139(6):1819–29.CrossRef
11.
go back to reference Januska MN, et al. Bronchoscopy in severe childhood asthma: Irresponsible or irreplaceable? Pediatr Pulmonol. 2020;55(3):795–802.CrossRef Januska MN, et al. Bronchoscopy in severe childhood asthma: Irresponsible or irreplaceable? Pediatr Pulmonol. 2020;55(3):795–802.CrossRef
12.
go back to reference Solé D, Aranda CS, Wandalsen GF. Asthma: epidemiology of disease control in Latin America - short review. Asthma Res Pract. 2017;3:4.CrossRef Solé D, Aranda CS, Wandalsen GF. Asthma: epidemiology of disease control in Latin America - short review. Asthma Res Pract. 2017;3:4.CrossRef
14.
go back to reference Eller MCN, et al. Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma? Pediatr Pulmonol. 2018;53(9):1208–17.CrossRef Eller MCN, et al. Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma? Pediatr Pulmonol. 2018;53(9):1208–17.CrossRef
15.
go back to reference Juniper EF, et al. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest. 1999;115(5):1265–70.CrossRef Juniper EF, et al. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest. 1999;115(5):1265–70.CrossRef
16.
go back to reference Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.CrossRef Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–73.CrossRef
17.
go back to reference Chatkin JM, et al. Compliance with maintenance treatment of asthma (ADERE study). J Bras Pneumol. 2006;32(4):277–83.CrossRef Chatkin JM, et al. Compliance with maintenance treatment of asthma (ADERE study). J Bras Pneumol. 2006;32(4):277–83.CrossRef
18.
go back to reference Roxo JP, et al. Portuguese-language version of the Asthma Control Test. J Bras Pneumol. 2010;36(2):159–66.CrossRef Roxo JP, et al. Portuguese-language version of the Asthma Control Test. J Bras Pneumol. 2010;36(2):159–66.CrossRef
19.
go back to reference Stocks J, et al. Plethysmographic measurements of lung volume and airway resistance. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J. 2001;17(2):302–12.CrossRef Stocks J, et al. Plethysmographic measurements of lung volume and airway resistance. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J. 2001;17(2):302–12.CrossRef
20.
go back to reference Quanjer H, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43.CrossRef Quanjer H, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43.CrossRef
21.
go back to reference Stocks J, Quanjer H. Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on Lung Volume Measurements. Eur Respir J. 1995;8(3):492–506.CrossRef Stocks J, Quanjer H. Reference values for residual volume, functional residual capacity and total lung capacity. ATS Workshop on Lung Volume Measurements. Eur Respir J. 1995;8(3):492–506.CrossRef
22.
go back to reference Dweik RA, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602–15.CrossRef Dweik RA, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602–15.CrossRef
23.
go back to reference Lex C, et al. Sputum induction in children with difficult asthma: safety, feasibility, and inflammatory cell pattern. Pediatr Pulmonol. 2005;39(4):318–24.CrossRef Lex C, et al. Sputum induction in children with difficult asthma: safety, feasibility, and inflammatory cell pattern. Pediatr Pulmonol. 2005;39(4):318–24.CrossRef
24.
go back to reference Pizzichini E, et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med. 1996;154(21):308–17.CrossRef Pizzichini E, et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med. 1996;154(21):308–17.CrossRef
25.
go back to reference Palomino AL, et al. Induced sputum in children and adolescents with asthma: safety, clinical applicability and inflammatory cells aspects in stable patients and during exacerbation. J Pediatr (Rio J). 2005;81(3):216–24.CrossRef Palomino AL, et al. Induced sputum in children and adolescents with asthma: safety, clinical applicability and inflammatory cells aspects in stable patients and during exacerbation. J Pediatr (Rio J). 2005;81(3):216–24.CrossRef
26.
go back to reference Woolhouse IS, Bayley DL, Stockley RA. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax. 2002;57(8):667–71.CrossRef Woolhouse IS, Bayley DL, Stockley RA. Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis. Thorax. 2002;57(8):667–71.CrossRef
27.
go back to reference Picinin IF, Camargos A, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung disease. J Bras Pneumol. 2010;36(3):372–85.CrossRef Picinin IF, Camargos A, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung disease. J Bras Pneumol. 2010;36(3):372–85.CrossRef
28.
go back to reference Poritz MA, et al. FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection. PLoS ONE. 2011;6(10):e26047.CrossRef Poritz MA, et al. FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection. PLoS ONE. 2011;6(10):e26047.CrossRef
29.
go back to reference Ferreira DS, et al. Airway pathology in severe asthma is related to airflow obstruction but not symptom control. Allergy. 2018;73(3):635–43.CrossRef Ferreira DS, et al. Airway pathology in severe asthma is related to airflow obstruction but not symptom control. Allergy. 2018;73(3):635–43.CrossRef
30.
go back to reference Dos Santos AB, et al. Immune cell profile in infants’ lung tissue. Ann Anat. 2013;195(6):596–604.CrossRef Dos Santos AB, et al. Immune cell profile in infants’ lung tissue. Ann Anat. 2013;195(6):596–604.CrossRef
31.
go back to reference Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2015;78:5. Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2015;78:5.
32.
go back to reference Crisford H, et al. Neutrophils in asthma: the good, the bad and the bacteria. Thorax. 2021;89:6. Crisford H, et al. Neutrophils in asthma: the good, the bad and the bacteria. Thorax. 2021;89:6.
33.
go back to reference Uhl B, et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016;128(19):2327–37.CrossRef Uhl B, et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016;128(19):2327–37.CrossRef
34.
go back to reference Grunwell JR, et al. Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immunol Pract. 2019;7(2):516–25.CrossRef Grunwell JR, et al. Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immunol Pract. 2019;7(2):516–25.CrossRef
35.
go back to reference Kolaczkowska E. The older the faster: aged neutrophils in inflammation. Blood. 2016;128(19):2280–2.CrossRef Kolaczkowska E. The older the faster: aged neutrophils in inflammation. Blood. 2016;128(19):2280–2.CrossRef
36.
go back to reference Ross KR, et al. Severe asthma during childhood and adolescence: A longitudinal study. J Allergy Clin Immunol. 2020;145(1):140–6.CrossRef Ross KR, et al. Severe asthma during childhood and adolescence: A longitudinal study. J Allergy Clin Immunol. 2020;145(1):140–6.CrossRef
37.
go back to reference Abe KC, Miraglia SG. Health Impact Assessment of Air Pollution in São Paulo, Brazil. Int J Environ Res Public Health. 2016;13:7.CrossRef Abe KC, Miraglia SG. Health Impact Assessment of Air Pollution in São Paulo, Brazil. Int J Environ Res Public Health. 2016;13:7.CrossRef
38.
go back to reference Turcotte H, et al. Variability of inflammatory cell counts on bronchial biopsies of normal subjects. Lung. 2003;181(1):9–21.CrossRef Turcotte H, et al. Variability of inflammatory cell counts on bronchial biopsies of normal subjects. Lung. 2003;181(1):9–21.CrossRef
39.
go back to reference Leggat JA, et al. Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization. J Allergy Clin Immunol. 2008;122(5):1014–21.CrossRef Leggat JA, et al. Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization. J Allergy Clin Immunol. 2008;122(5):1014–21.CrossRef
40.
go back to reference Van Rensen EL, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med. 2005;172(7):837–41.CrossRef Van Rensen EL, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med. 2005;172(7):837–41.CrossRef
41.
go back to reference Bradding P, Brightling C. Mast cell infiltration of airway smooth muscle in asthma. Respir Med. 2007;101(5):1045.CrossRef Bradding P, Brightling C. Mast cell infiltration of airway smooth muscle in asthma. Respir Med. 2007;101(5):1045.CrossRef
42.
go back to reference Balzar S, et al. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Respir Crit Care Med. 2005;171(5):431–9.CrossRef Balzar S, et al. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Respir Crit Care Med. 2005;171(5):431–9.CrossRef
43.
go back to reference Waern I, et al. Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dust-mite induced airway inflammation. Mucosal Immunol. 2013;6(5):911–20.CrossRef Waern I, et al. Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dust-mite induced airway inflammation. Mucosal Immunol. 2013;6(5):911–20.CrossRef
44.
go back to reference Grainge CL, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006–15.CrossRef Grainge CL, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006–15.CrossRef
Metadata
Title
Bronchial eosinophils, neutrophils, and CD8 + T cells influence asthma control and lung function in schoolchildren and adolescents with severe treatment-resistant asthma
Authors
Miriam Cardoso Neves Eller
Karina Pierantozzi Vergani
Beatriz Mangueira Saraiva-Romanholo
Natália de Souza Xavier Costa
Jôse Mára de Brito
Leila Antonangelo
Caroline Silvério Faria
Joaquim Carlos Rodrigues
Thais Mauad
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2022
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-022-02259-4

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