Background Pneumococcal pneumonia is a leading cause of death, particularly affecting those with chronic respiratory disease. Observational studies suggest increased nasopharyngeal colonisation rates with S.pneumoniae in asthma, and lower specific antibody levels. Objectives Using experimental human pneumococcal challenge, we examined the acquisition and kinetics of nasopharyngeal colonisation of Streptococcus pneumoniae serotype 6B. We also aimed to dissect associated mucosal and systemic immune responses and immunizing effect of carriage. Methods Fifty participants with asthma well-controlled on moderate inhaled corticosteroid doses were challenged with pneumococcus, and a subset of colonized individuals were re-challenged 6-11 months later with the same pneumococcal isolate . Colonisation rates (from nasal wash), systemic antibody levels and mucosal cellular and cytokine responses were compared to 151 healthy controls. Measurements and Main Results Colonisation rates were 28/50 (56%) and 68/151 (45%) in those with asthma and controls respectively, p=0.17. Duration of colonisation was shorter in people with asthma (median 14 days vs 29 days, p=0.03) but of similar density. Body mass index was higher in colonised compared with non-colonised asthma individuals (median 24.7 [IQR 24.1-29.0] and 23.5 [20.1-26.4] respectively, p=0.019). Despite an increase in pneumococcal capsular and protein antibodies after colonisation, 4/12 asthmatic individuals became colonised again upon re-challenge. Nasal neutrophil and T cell levels, in particular mucosa associated invariant T (MAIT) cells were decreased in people with asthma compared to healthy controls (median 9.4, [IQR 5.0-13.3 %] of CD8+ T cells) vs median 15.8, [IQR 9.9-25.9 %] of CD8+ T cells respectively (p=0.0047). Most nasal cytokines were also reduced in asthmatics. In both groups, colonisation led to recruitment of monocytes and granulocytes to the nasal mucosa. Conclusions: Nasopharyngeal colonisation was of shorter duration in those with asthma compared to controls, although acquisition rates were not different. Rates of colonisation were higher with increasing BMI in individuals with asthma. Despite a baseline reduction in mucosal immune cells and cytokines in asthmatics with corticosteroids, colonisation led to cellular recruitment in both groups. Colonisation was not associated with protection from homologous re-challenge in individuals with asthma, in contrast to healthy volunteers. Clinical Implication: People with asthma on inhaled corticosteroids have an increased likelihood of pneumococcal infection secondary to reduced mucosal immune responses from nasopharyngeal colonisation and a lack of protection from re-exposure.

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成人哮喘实验定殖后细菌清除的机制和动力学

背景肺炎球菌性肺炎是导致死亡的主要原因，特别是影响那些患有慢性呼吸系统疾病的人。观察性研究表明，哮喘患者中肺炎链球菌的鼻咽定植率增加，特异性抗体水平降低。目的使用实验性人类肺炎球菌攻击，我们检查了肺炎链球菌血清型6B的鼻咽定殖的获得和动力学。我们还旨在剖析相关的粘膜和全身免疫反应以及运输的免疫效果。方法用适度吸入糖皮质激素中等剂量控制哮喘的50名参与者接受肺炎球菌攻击，并在6-11个月后用相同的肺炎球菌分离株再次挑战一部分定植的个体。定殖率（来自鼻腔冲洗）将全身抗体水平以及粘膜细胞和细胞因子反应与151名健康对照进行了比较。测量结果和主要结果哮喘患者和对照组的定殖率分别为28/50（56％）和68/151（45％），p = 0.17。哮喘患者的定植时间较短（中位14天vs 29天，p = 0.03），但密度相似。殖民地居民的体重指数高于非殖民地哮喘个体（中位数分别为24.7 [IQR 24.1-29.0]和23.5 [20.1-26.4]，p = 0.019）。尽管定植后肺炎球菌荚膜和蛋白质抗体增加，但再次挑战后4/12哮喘个体再次定居。与健康对照组相比，哮喘患者的鼻中性粒细胞和T细胞水平，尤其是粘膜相关的不变T（MAIT）细胞降低（中位数9.4，CD8 + T细胞的[IQR 5.0-13.3％]相对于CD8 + T细胞的中位数15.8 [IQR 9.9-25.9％]（p = 0.0047）。哮喘患者中大多数鼻细胞因子也减少。在两组中，定植导致单核细胞和粒细胞募集到鼻粘膜。结论：与哮喘相比，哮喘患者的鼻咽部定植时间更短，尽管获得率没有差异。哮喘患者中随着BMI的增加，定植率更高。尽管使用皮质类固醇的哮喘患者的粘膜免疫细胞和细胞因子基线降低，但定植导致两组中的细胞募集。与健康志愿者相反，在哮喘患者中，定植与防止同源再攻击无关。临床意义：