Pathfinder: Determining the efficacy of plasmapheresis as a treatment for patients with chronic Pseudomonas infections and inhibitory antibodies

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Chronic Pseudomonas aeruginosa lung infections occur in patients suffering from cystic fibrosis (CF), non-CF bronchiectasis and chronic obstructive pulmonary disorder (COPD). Such infections lead to chronic inflammation, deteriorating lung function and increased morbidity and mortality. Once colonisation is established, Pseudomonas is almost impossible to remove by current methods. Methods to ameliorate infection would positively impact on patient quality of life and longevity.Antibody normally protects against infection. However, recently we identified that some patients with chronic Pseudomonas lung infections had a type of antibody that actually protects their colonising bacteria from killing by the immune system. These inhibitory antibodies were found to prevent both serum and cell killing of patient's Pseudomonas cognate strains. The inhibitory antibodies were identified as IgG2 specific to lipopolysaccharide, specifically the O-antigen component. We hypothesise that these antibodies exert their inhibitory effect either by depositing complement away from the bacterial membrane preventing membrane attack complex insertion or by blocking access of protective antibody. Importantly, we found patients with high titres of inhibitory antibodies had worse lung function than patients infected with Pseudomonas who had normal serum killing. Based on our data, we opted for a radical treatment programme for one critically ill patient who had inhibitory antibodies. Using plasmapheresis we removed all serum protein, including the inhibitory IgG2, and replaced it with IVIg that we had demonstrated could mediate serum killing of the patient's isolate. The patient improved dramatically after plasmapheresis and Pseudomonas remained undetectable in the sputum for a significant period of time. A second critically ill patient has recently undergone a similar treatment regime with similar success. Patients receiving this treatment required fewer days in hospital, fewer treatment interventions such as intravenous antibiotics and reported a much reduced level of symptoms. Excitingly, this offers a novel treatment for critically ill patients with inhibitory antibodies, however many vital questions remain unanswered. This project is vital to determine the clinical relevance of inhibitory antibodies in patients with chronic Pseudomonas lung infections and to identify whether plasma exchange is a viable treatment option for this novel problem. The project will do this using two approaches; first, by determining the prevalence of inhibitory antibodies in a large cohort of patients with both CF and non-CF bronchiectasis. This will determine the scale of the problem as well as thoroughly investigate the link between inhibitory antibodies and health degradation. Secondly, the project will investigate the treatment option by conducting a longitudinal study on patients currently being treated by plasma exchange. We will identify if previous plasma exchange treatments were successful due to removal of inhibitory antibodies alone, or if other factors were at play. We will investigate whether increases in IgG2 correlate with reappearance of the strain and worsening disease. We will also use next-generation sequencing to determine if strain replacement is being driven by plasmapheresis, as this would support the theory that the removal of inhibitory antibody is having a positive impact on the ability of the immune system to control infection post plasma exchange. Finally, this project aims to optimise a diagnostic test for detecting the presence of inhibitory antibodies.