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Experimental Human Pneumococcal Challenge: Effect of Asthma on Human Responses to Pneumoccous

Zaidi, Seher (2020) Experimental Human Pneumococcal Challenge: Effect of Asthma on Human Responses to Pneumoccous, Thesis (Doctoral), Liverpool School of Tropical Medicine.

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Pneumococcal pneumonia is a leading cause of death globally, and susceptibility to invasive and pulmonary infection is increased in chronic respiratory conditions. Pneumococcal colonisation of the nasopharynx necessarily precedes disease, but the relationship of colonisation with Streptococcus pneumoniae and chronic respiratory disease (such as asthma) is unknown. Asthma is a heterogenous condition representing several phenotypes which have corresponding clinical characteristics and responses to therapy. Immune responses mediated by cytokines from cells such T helper cells 2 (Th2) and Th17 lead to airway inflammation. Both this inflammatory pathology, and the treatment of it (with inhaled corticosteroids) potentially affect nasopharyngeal colonisation with S.pneumoniae. Hypothetically, airway inflammation might increase the potential for bacterial attachment, or increase bacterial clearance, or both. As nasopharyngeal colonisation is immunogenic in healthy adults, the balance of these opposing mechanisms may impact the resulting immune response. We have safely used the experimental human pneumococcal challenge (EHPC) model in healthy individuals to study nasopharyngeal colonisation and its associated mucosal and systemic immune responses.

Using experimental pneumococcal challenge in people with asthma, I examined the acquisition of nasopharyngeal colonisation of Streptococcus pneumoniae, its association with clinical characteristics, and systemic immune responses. I compared the results with historic data from earlier EHPC studies of healthy controls.

I enrolled people with physician-diagnosed, well-controlled asthma on maintenance inhaled corticosteroids. Participants were challenged with pneumococcus serotype 6B, as this is not isolated from nasal samples within the local community. Blood and mucosal samples were collected at baseline and on days 2,7, 9, 14, 22 and 29 after challenge. The results were compared to healthy controls from 4 experimental human challenge studies, with 2 performed concurrently and 2 in previous years.

Main Results
Experimental colonisation rates were not significantly increased in people with asthma compared to healthy controls. The number of colonised participants (nasal wash positive for bacterial culture at any time point) was 28 (56%) in asthma vs 68 (45%) in healthy controls (Pearson’s chi square p=0.178). The density calculated using the area under time cure (AUC) was similar in people with asthma compared to healthy controls (median [IQR] asthma 63.49 [14.04-116.3] vs healthy controls 81.18 [48.15-104.5] Mann Whitney U test p=0.060). Acquisition of colonisation was independent of baseline characteristics such as blood eosinophils and fractional exhaled nitric oxide levels.
The duration of experimental colonisation was significantly shorter in asthma compared to healthy controls (median [IQR] 14 [7-29] vs 29[14-29]) p=0.034 Mann Whitney U test. Colonisation led to an increase in IgG titres to capsular polysaccharide and pneumococcal proteins in people with asthma as previously described in healthy controls. Body mass index correlated positively with likelihood of colonisation in people with asthma. Median BMI for the whole cohort was 24.6 (IQR) (21.6-27.5), with colonised participants (nasal wash positive for bacterial culture at any time point) having a higher BMI median 24.7 (24.1-29.0) vs 23.5 (20.1-26.4) in non-colonised (p=0.019 independent samples t test).

Experimental colonisation is not affected by clinical characteristics of asthma, and it is positively correlated with a high BMI. The rate and density of experimental nasopharyngeal colonisation in people with asthma are similar as seen in healthy controls. The duration of colonisation is significantly reduced in people with asthma compared to healthy controls, with a similar immunogenic effect as seen in healthy controls. Interventions to reduce the likelihood of severe and invasive pneumococcal disease, to which people with asthma are more prone, could be targeted at specific sub-groups. Further investigation could suggest if those with higher BMI should have a lower threshold for vaccination.

Item Type: Thesis (Doctoral)
Subjects: WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 204 Pneumococcal pneumonia. Staphylococcal pneumonia
WF Respiratory System > WF 140 Diseases of the respiratory system (General)
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Depositing User: Lynn Roberts-Maloney
Date Deposited: 26 Mar 2021 12:00
Last Modified: 26 Jun 2021 01:02


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