Mechanisms and kinetics of bacterial clearance after experimental colonisation in adults with asthma

Abstract

AbstractBackgroundPneumococcal 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.ObjectivesUsing 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.MethodsFifty 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 ResultsColonisation 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.ConclusionsNasopharyngeal 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: (single sentence)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.Capsule SummaryEpidemiological studies show that people with asthma are more likely to have nasal colonisation with S. pneumoniae, which may proceed to infection such as pneumonia and invasive pneumococcal disease. This study investigates the mechanisms underlying pneumococcal colonisaion and its effect on subsequent pneumococcal encounters.