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. 2020 Oct;146(4):840-850.e7.
doi: 10.1016/j.jaci.2020.03.021. Epub 2020 Apr 10.

Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD

Jie Zhu  1 , Patrick Mallia  2 , Joseph Footitt  2 , Yusheng Qiu  1 , Simon D Message  2 , Tatiana Kebadze  1 , Julia Aniscenko  1 , Peter J Barnes  1 , Ian M Adcock  1 , Onn M Kon  2 , Malcolm Johnson  3 , Marco Contoli  4 , Luminita A Stanciu  1 , Alberto Papi  5 , Peter K Jeffery  1 , Sebastian L Johnston  6
Affiliations

Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD

Jie Zhu et al. J Allergy Clin Immunol. 2020 Oct.

Abstract

Background: Respiratory viral infection causes chronic obstructive pulmonary disease (COPD) exacerbations. We previously reported increased bronchial mucosa eosinophil and neutrophil inflammation in patients with COPD experiencing naturally occurring exacerbations. But it is unclear whether virus per se induces bronchial mucosal inflammation, nor whether this relates to exacerbation severity.

Objectives: We sought to determine the extent and nature of bronchial mucosal inflammation following experimental rhinovirus (RV)-16-induced COPD exacerbations and its relationship to disease severity.

Methods: Bronchial mucosal inflammatory cell phenotypes were determined at preinfection baseline and following experimental RV infection in 17 Global Initiative for Chronic Obstructive Lung Disease stage II subjects with COPD and as controls 20 smokers and 11 nonsmokers with normal lung function. No subject had a history of asthma/allergic rhinitis: all had negative results for aeroallergen skin prick tests.

Results: RV infection increased the numbers of bronchial mucosal eosinophils and neutrophils only in COPD and CD8+ T lymphocytes in patients with COPD and nonsmokers. Monocytes/macrophages, CD4+ T lymphocytes, and CD20+ B lymphocytes were increased in all subjects. At baseline, compared with nonsmokers, subjects with COPD and smokers had increased numbers of bronchial mucosal monocytes/macrophages and CD8+ T lymphocytes but fewer numbers of CD4+ T lymphocytes and CD20+ B lymphocytes. The virus-induced inflammatory cells in patients with COPD were positively associated with virus load, illness severity, and reductions in lung function.

Conclusions: Experimental RV infection induces bronchial mucosal eosinophilia and neutrophilia only in patients with COPD and monocytes/macrophages and lymphocytes in both patients with COPD and control subjects. The virus-induced inflammatory cell phenotypes observed in COPD positively related to virus load and illness severity. Antiviral/anti-inflammatory therapies could attenuate bronchial inflammation and ameliorate virus-induced COPD exacerbations.

Keywords: Rhinovirus infection; chronic obstructive pulmonary disease exacerbation; eosinophils; inflammation.

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Figures

Fig 1
Fig 1
Immunohistochemistry-stained cells are seen as red fuchsin or brown diaminobenzidinen positivity: RV-16 infection on day 7 increased numbers of (A) eosinophils, (B) neutrophils, (C) CD68+ (arrows), (D) CD8+, (E) CD4+, and (F) CD20+ (arrows) cells in bronchial mucosa of subjects with COPD compared with their baseline numbers of (G) eosinophils, (H) neutrophils, (I) CD68+ (arrows), (J) CD8+, (K) CD4+, and (L) CD20+ (arrows) cells. M, Negative control shows an absence of signal (internal scale bar = 20 μm for all).
Fig 2
Fig 2
Counts for subepithelial (A) eosinophils, (B) CD68+ monocytes/macrophages, (C) CD8+ and (D) CD4+ T lymphocytes, (E) CD20+ B lymphocytes, and (F) tryptase+ mast cells in bronchial biopsies of healthy nonsmokers, healthy smokers, and subjects with COPD at baseline and day 7 after RV-16 infection. The data are expressed as the number of positive cells per mm2 of sub. G, Changes in counts of subepithelial eosinophils from baseline to day 7 postinfection in bronchial biopsies of healthy nonsmokers, healthy smokers, and subjects with COPD. The data are expressed as change in the number of eosinophils per mm2 of sub. Triangles show individual counts, and arrows/horizontal bars show median values (Wilcoxon matched pairs test and Mann-Whitney U test).
Fig 3
Fig 3
Counts for epithelial (A) neutrophils, (B) CD68+ monocytes/macrophages, and (C) CD4+, (D) CD20+, and (E) CD8+ lymphocytes in bronchial biopsies of healthy nonsmokers, healthy smokers, and subjects with COPD at baseline and day 7 after RV-16 infection. The data are expressed as the number of positive cells per 0.1 mm2 of epi. Triangles show individual counts, and arrows show median values (Wilcoxon matched pairs test and Mann-Whitney U test).
Fig 4
Fig 4
Blood eosinophils and sputum eosinophil-related soluble mediators in subjects with COPD during experimental RV infection: (A) blood eosinophil percentages at baseline and day 7 postinfection and (B) eotaxin and (C) eotaxin-3 in induced sputum at baseline and day 3 to 42 postinfection. Triangles show individual counts, and horizontal bars show median values (Wilcoxon matched pairs test). BASE, Baseline.
Fig 5
Fig 5
Correlations, in subjects with COPD, between the numbers of subeosinophils on day 7 postinfection and (A) peak sputum virus load, (B) peak breathlessness scores, and (C) reduction in peak expiratory flow (% fall from baseline), recorded on day 9 postinfection, (D) between BAL virus load and subneutrophils on day 7 postinfection; between counts of (E) epi- and (F) sub-neutrophils on day 7 and prebronchodilator FEV1% predicted at day 9 (Spearman rank correlation, n = 17 or 9). BAL, Bronchoalveolar lavage.
Fig 6
Fig 6
Correlations, in subjects with COPD, between the numbers of subepithelial eosinophils at day 7 postinfection and peak sputum: (A) neutrophils, (B) CXCL8/IL-8, (C) IL-1β, (D) TNF, (E) pentraxin-3, (F) LL-37, and (G) neutrophil elastase (Spearman rank correlation, n = 17 for all).
Figure E1
Figure E1
In subjects with COPD, correlations between the numbers of (A) sub-CD68+ and (B) CD4+ on day 7 and peak nasal lavage virus load, (C) between sub-CD20+ on day 7 and peak sputum virus load, and (D) between sub-CD8+ cells on day 7 and BAL virus load (Spearman rank correlation, n = 17 or 9).
Figure E2
Figure E2
In subjects with COPD, correlations between the numbers of (A) sub-CD8+ and (B) CD20+ cells on day 7 postinfection and peak breathlessness scores, (C) between counts of sub-CD68+ cells and peak lower respiratory tract symptom score, and between the numbers of (D) sub-CD8+, (E) CD4+, and (F) CD20+ cells on day 7 and prebronchodilator FEV1% predicted at day 9 (Spearman rank correlation, n = 17).
Figure E3
Figure E3
Correlations between smoking pack-years and numbers of (A) baseline epi-CD68+ and (B) CD8+ cells in subjects with COPD and (C) baseline sub-CD8+ cell counts, (D) epi- and (E) sub-tryptase+ mast-cell counts in healthy smokers (Spearman rank correlation, n = 17 for COPD and n = 21 for healthy smokers).
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