Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence’s contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure.

Nagata M, et al. Asia Pac Allergy. 2020 Apr;10:e14. https://doi.org/10.5415/apallergy.2020.10.e14

Severe asthma is a complex disease with heterogeneous features and involves type 2 airway inflammation, including eosinophil accumulation. Surrogate biomarkers, fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (b-EOS), may predict eosinophilic airway inflammation. Here we investigated clinical characteristics of severe asthma phenotype using a combined analysis of FeNO and b-EOS. This retrospective study examined clinical data of patients with severe asthma (N = 107; median age, 64 years) treated at Saitama Medical University Hospital from 2009 to 2016. Thresholds of FeNO and b-EOS for sputum eosinophil ratio ≥2% were determined using receiver operating characteristic curve (ROC) analysis. Clinical characteristics were analyzed after classifying patients into four subgroups according to these thresholds. Of 39 induced sputum samples examined, ROC area under the curve for predicting sputum eosinophilia was 82.0% (p = 0.001) for b-EOS and 77.0% (p = 0.006) for FeNO at optimal cut-off values of ≥300/μL and ≥25 ppb, respectively. The number of sensitized allergens was higher in the high FeNO/low b-EOS and high FeNO/high b-EOS subgroups (p < 0.05). The prevalence of chronic sinusitis was higher in the low FeNO/high b-EOS and high FeNO/high b-EOS subgroups (p = 0.04). The high FeNO/high b-EOS subgroup included the largest proportion (approximately 40%) of patients experiencing frequent severe exacerbations. Both low FeNO/low b-EOS and high FeNO/low b-EOS subgroups showed less severe exacerbations. Combined evaluation of FeNO and b-EOS can identify patients with frequent exacerbations and stratify the appropriate therapy for type 2 inflammation-predominant severe asthma.

Eosinophils recognize various stimuli, such as cytokines, chemokines, immunoglobulins, complement, and external pathogens, resulting in their accumulation in mucosal tissues and the progression of inflammation. Eosinophils are also involved in innate Th2-type immune responses mediated through endogenous danger signals, including IL-33, uric acid (UA), or ATP, in non-sensitized mice exposed to environmental allergens. However, the mechanism involved in eosinophil responses to these danger signals remains insufficiently understood. We examined migration, adhesion, superoxide production and degranulation of human eosinophils. Isolated eosinophils were incubated with monosodium urate (MSU) crystals and ATPγS, a non-hydrolysable ATP analogue. To determine the involvement of P2 or P2Y2 receptors in eosinophil responses to UA and ATP, eosinophils were preincubated with a pan-P2 receptor inhibitor, oxidized ATP (oATP), or anti-P2Y2 antibody before incubation with MSU crystals or ATPγS. MSU crystals induced adhesion of eosinophils to recombinant human (rh)-ICAM-1 and induced production of superoxide. oATP abolished eosinophil responses to MSU crystals, suggesting involvement of endogenous ATP and its receptors. Furthermore, exogenous ATP, as ATPγS, induced migration of eosinophils through a model basement membrane, adhesion to rh-ICAM-1, superoxide generation, and degranulation of eosinophil-derived neurotoxin (EDN). oATP and anti-P2Y2 significantly reduced these eosinophil responses. ATP serves as an essential mediator of functional responses in human eosinophils. Eosinophil responses to ATP may be implicated in airway inflammation in patients with asthma.

Asthma is a disease encompassing a variety of contributing factors. Phenotyping of asthma based on the profile of accumulated granulocytes in the airways has been performed to explore the mediators involved in allergic bronchial inflammation. The aim of this study was to clarify the characteristics of the CXC chemokine superfamily induced by IFN-γ, namely CXCR3 ligands, in the airways of patients with asthma stratified by the differential proportion of granulocytes in sputum. Sputum was induced in 39 adult patients with asthma and 12 healthy subjects. Sputum samples were analyzed for total cell counts and differentials, and concentrations of IFN-γ–inducible protein 10 kDa (IP-10, CXCL10), monokine induced by IFN-γ (Mig, CXCL9), IFN-inducible T cell a chemoattractant (I-TAC, CXCL11), and IL-8 in the supernatants were assayed by ELISA. Sputum concentrations of IP-10, Mig, and IL-8 were significantly higher in asthma than in healthy subjects. IP-10, Mig, and IL-8 were significantly higher in the mixed granulocyte subtype (eosinophils ≥ 2 % and neutrophils ≥ 40 % in sputum) than in healthy subjects. Additionally, IP-1 0 was significantly higher in the mixed granulocyte subtype than in eosinophil-predominant or neutrophil-predominant subtype (eosinophil percentage ≥ 2 % or neutrophil percentage ≥ 40 %). Mig and IL-8 were significantly higher in the mixed granulocyte subtype than in the paucigranulocyte subtype (eosinophils < 2 % and neutrophils < 40 % in sputum). I-TAC was not different between healthy subjects and asthmatics or granulocyte subtypes. All CXCR3 ligands were significantly associated with the composite of the eosinophil and neutrophil ratio in patients with asthma. Only Mig was significantly correlated with the total eosinophil and neutrophil ratio in patients with asthma on adjusted partial correlation analysis. Mig and IL-8 were significantly negatively correlated with forced expiratory volume in 1 s % predicted (% FEV1) in patients with asthma. CXCR3 ligands may serve as potent promoters in eosinophilic and neutrophilic airway inflammation in asthma.

Background: Allergen immunotherapy (AIT) is a specific treatment of administering clinically important allergens to patients who have allergic diseases. In Japan, the standardized house dust mite (HDM) allergen for subcutaneous immunotherapy (SCIT) was approved in 2015, and we then introduced rush-immunotherapy (rush-IT) using the standardized HDM allergen for HDM-sensitive asthmatics. However, little data are available on the safety and effectiveness of rush-HDM-IT, especially for Japanese asthmatics. Objective: The objective of this study was to examine the safety and clinical effectiveness of rush-IT using the standardized HDM for HDM-sensitive Japanese asthmatics. Methods: Thirteen HDM-sensitive asthmatics who received rush-HDM-IT and 12 HDM-sensitive asthmatic controls were enrolled. To evaluate the safety, the number of systemic reaction (SR) events, including anaphylaxis, was assessed. To evaluate the effectiveness, changes in the treatment step, dose of inhaled corticosteroid, and asthma control after rush-HDM-IT and the subsequent maintenance SCIT were assessed. Changes in the HDM-induced production of type 2 cytokines from peripheral blood mononuclear cells were also evaluated. Results: Among the 12 patients who received rush-IT, 4 (30.7%) experienced a SR and 3 (23.1%) experienced anaphylaxis. However, the anaphylaxis was not severe (grade 3) in all cases, and they recovered in a short time. The treatment step of asthma was better and the dose of inhaled corticosteroid was lower in the rush-HDM-IT group than in the control group. The HDM-induced production of both interleukin (IL)-5 and IL-13 from peripheral blood mononuclear cells was significantly lower in the rush-HDM-IT group than in the control group. Conclusion: Rush-HDM-IT can be performed relatively safely in Japanese asthmatics. Furthermore, rush-HDM-IT and the subsequent maintenance SCIT provided clinical improvement in asthma patients, and was accompanied by the suppression of HDM-specific Th2-mediated systemic immune responses.