Invasive disease by Haemophilus influenzae in Sweden in the era of the H. influenzae type b vaccine

University dissertation from Department of Laboratory Medicine, Malmö, Faculty of Medicine, Lund University

Abstract: What is the current status of Haemophilus influenzae as an agent of invasive infection in Sweden? H. influenzae type b (Hib) used to be a common cause of meningitis, epiglottitis and severe sepsis in young children. In the late 1980’s an effective conjugated vaccine against Hib was developed and a dramatic fall in Hib incidence was observed in countries that implemented vaccination. This includes Sweden, where the vaccine was implemented in 1992. Since the mid 1990’s, scattered international reports have suggested increasing incidences of invasive disease caused by non-type b isolates of H. influenzae. A few of these reports have suggested serotype replacement. In order to answer the initial question, we studied the epidemiology, the clinical burden and antimicrobial resistance of invasive H. influenzae in Sweden 1997-2010. Two aspects of the pathogenesis of invasive H. influenzae disease were addressed; bacterial binding to the extracellular matrix and the role of complement regulator binding in invasive disease. A case report of a severe invasive H. influenzae type f infection, including an examination of contributing host factors, is also presented. Our results suggest that invasive disease by H. influenzae has not disappeared, but the epidemiology has radically changed. We found no support for serotype replacement in young children. In adults, and especially elderly adults, the incidence of invasive disease by non-typeable H. influenzae (NTHi) increased significantly during the study period. The results also suggest an increased incidence of invasive disease by H. influenzae type f (Hif), and type f is the most common serotype in Sweden today. Cases of invasive disease by non-type b isolates that occurred in healthy adults were often severe, suggesting the existence of hypervirulent non-type b strains. The β-lactam resistance of invasive H. influenzae isolates increased during the study period, due to an increase of β-lactamase negative β-lactam resistant NTHi. A clonal expansion of a β-lactamase negative ampicillin resistant (BLNAR) clone, frequently found in invasive disease, was suggested. The ability of H. influenzae to bind laminin, and anchor the extracellular matrix through the adhesin Protein E was confirmed. Binding to complement regulators was not higher in invasive as compared to nasopharyngeal NTHi isolates, and thus did not seem central for invasive capacity. Speculation, but no comprehensive conclusion as to what host factors relate to invasive disease by H. influenzae in adults was possible. The results suggest that the vaccination against H. influenzae type b remains very effective 20 years after it was introduced, but that continued surveillance of incidence and antimicrobial resistance of invasive Haemophilus disease is warranted. The results also suggest that ongoing research should focus on non-typeable H. influenzae, which today dominates all types of H. influenzae infections.

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