Metabolomic fingerprinting and systemic inflammatory profiling of asthma COPD overlap (ACO)

Abstract

Background: Asthma-COPD overlap (ACO) refers to a group of poorly studied and characterised patients reporting with disease presentations of both asthma and COPD, thereby making both diagnosis and treatment challenging for the clinicians. They exhibit a higher burden in terms of both mortality and morbidity in comparison to patients with only asthma or COPD. The pathophysiology of the disease and its existence as a unique disease entity remains unclear. The present study aims to determine whether ACO has a distinct metabolic and immunological mediator profile in comparison to asthma and COPD. Methods: Global metabolomic profiling using two different groups of patients [discovery (D) and validation (V)] were conducted. Serum samples obtained from moderate and severe asthma [n = 34(D); n = 32(V)], moderate and severe COPD [n = 30(D); 32(V)], ACO patients [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using gas chromatography mass spectrometry (GC-MS). Multiplexed analysis of 25 immunological markers (IFN-γ (interferon gamma), TNF-α (tumor necrosis factor alpha), IL-12p70 (interleukin 12p70), IL-2, IL-4, IL-5, IL-13, IL-10, IL-1α, IL-1β, TGF-β (transforming growth factor), IL-6, IL-17E, IL-21, IL-23, eotaxin, GM-CSF (granulocyte macrophagecolony stimulating factor), IFN-α (interferon alpha), IL-18, NGAL (neutrophil gelatinase-associated lipocalin), periostin, TSLP (thymic stromal lymphopoietin), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3 like 1) and IL-8) was also performed in the discovery cohort. Results: Eleven metabolites [serine, threonine, ethanolamine, glucose, cholesterol, 2-palmitoylglycerol, stearic acid, lactic acid, linoleic acid, D-mannose and succinic acid] were found to be significantly altered in ACO as compared with asthma and COPD. The levels and expression trends were successfully validated in a fresh cohort of subjects. Thirteen immunological mediators including TNFα, IL-1β, IL-17E, GM-CSF, IL-18, NGAL, IL-5, IL-10, MCP-1, YKL-40, IFNγ, IL-6 and TGF-β showed distinct expression patterns in ACO. These markers and metabolites exhibited significant correlation with each other and also with lung function parameters.

Metabolic Phenotypes in Asthmatic Adults: Relationship with Inflammatory and Clinical Phenotypes and Prognostic Implications

“…A similar discriminatory capacity between asthma and COPD was also observed in other metabolomics studies, using an electronic nose [ 126 ] and peripheral blood [ 127 , 128 ]. In this context, a study involving metabolomic analysis of exhaled air using an eNose in 60 asthma patients (21 with fixed airway obstruction, 39 with “classical”, reversible airway obstruction) and 40 COPD (GOLD stages II–III) showed that external validation of global breath-prints had high accuracy (88% between fixed asthma and COPD; 83% between classical asthma and COPD) for discriminating between the two diseases [ 126 ].…”

“…In another study, Ghosh et al [ 128 ] studied metabolic and immunological profiles in ACO, asthma and COPD. As previously mentioned, identification of metabolites was performed using non-targeted metabolomics with the GC–MS technique.…”

“…Finally, this study also showed that stearic acid expression was increased in asthma when compared with ACO and COPD, which indirectly may suggest that, similarly to linoleic acid, stearic acid may be a biomarker of involvement in the differentiation of T helper 2 (Th2) cells and T2-related inflammatory response in asthmatic individuals. Furthermore, a heatmap 2D correlation matrix in the previous study showed a significant negative correlation between serine, ethanolamine, threonine, glucose, cholesterol and succinic acid with tumor necrosis factor α (TNF-α), and non-significant negative correlations between interleukin-1β (IL-1β) and neutrophil gelatinase-associated lipocalin (NGAL) with threonine, MCP-1, YKL-40, IFN-γ and IL-6 with serine and cholesterol [ 128 ]. On the other hand, stearic acid and linoleic acid have been shown to positively correlate with TNF-α and this may be relevant since this is a pro-inflammatory cytokine that can also have increased expression not only in COPD but also in some asthmatic patients, namely in severe asthma, including refractory asthma [ 101 ] and neutrophilic severe asthma (which may be refractory or not), where, in fact, this cytokine may contribute to the neutrophilic infiltrate in the airways [ 129 ].…”

Update on Asthma–COPD Overlap (ACO): A Narrative Review

“…63 Recently, it was reported that 11 metabolites: serine, threonine, ethanolamine, glucose, cholesterol, 2-palmitoylglycerol, stearic acid, lactic acid, linoleic acid, D-mannose, and succinic acid, were found to be significantly altered in ACO as compared with asthma or COPD. 64 This provides novel insights into metabolic pathways and inflammatory mediators involved in the mechanisms underlying ACO and how these processes may be linked to each other and also with the pulmonary function impairment. Lastly, there are epigenetic changes showing a characteristic expression profile of miRNAs in ACO, distinctive from asthma and COPD.…”

Asthma-COPD Overlap (ACO) PRO-CON Debate. ACO: Call Me by My Name

“…These consensus definitions included all patients with ACO irrespective of their specific phenotype [11,17,18]. This is particularly relevant because, irrespective of the phenotype, the concept of ACO identifies a group of patients that have some specific genetic [13,19] and epigenetic background [20], differential sputum, serum and exhaled biomarkers [21][22][23] and metabolomics [24]. They also present specific symptoms, different outcomes compared to asthma and COPD and specific response to treatment; basically, they should receive long-acting bronchodilators and ICS [14,19,25].…”