Thesis for doctoral degree (Ph.D.) 2007 Molecular epidemiology of pneumococcal carriage and invasive disease Karin Sjöström.

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1 Thesis for doctoral degree (Ph.D.) 2007 Thesis for doctoral degree (Ph.D.) 2007 Molecular epidemiology of pneumococcal carriage and invasive disease Karin Sjöström Molecular Epidemiology of Pneumococcal Carriage and Invasive Disease Karin Sjöström

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38 suggested a low invasive disease potential, i.e. was mainly found in carriage. Isolates could be divided into two groups with one group mainly causing invasive disease, including serotype 1, 4, 7F and 9V, and rarely found among carriers. Serotypes and clones belonging to the second group were found both in invasive disease and among carriers, such as serotype 6B, 14, 6A and 19F where the two latter ones were mainly found among carriers, Figure 4. 24F 31 22F 20 12F 3% 8 4% 1 7% 33F 17F 2 35A 14 12% 7F 8% 18C 16 24F 35B 3% 4% 9N 19A 15B 38 23A 7 3 NT 21 6A 17% 35F 4 12% 9V 7% 6B 5% 11A 15C 9V 10 3% 19F 17% 15C 15B 10C 3 5% 14 7% NT 23A 6A 35F 38 10A 19F 18C 9N 3% 11A 3% 19A 5% 23F 5% 23F 13% 6B 13% Figure 4. Serotype distribution among invasive and carriage isolates. The left circle shows the serotype distribution among the invasive isolates and the right shows the distribution among the carriage isolates. Red colour indicates unique serotypes for respective group. The blue indicates serotypes found among both invasive and carriage isolates. The types causing invasive disease, 1, 4, 7F and 9V, were highly clonally related. All 7F isolates belonged to the same clone and all isolates analysed with MLST revealed the same sequence type, ST191. Among the serotype 1 isolates, the majority were found to belong to the same clonal cluster, with ST228/306 according to MLST analysis. No carriage isolates of serotype 1 were found, and only four (out of 27) carriage isolates of serotype 7F were identified. This is in concordance with a meta analysis of seven different studies by Brueggemann et al where serotype/serogroup 1 and 7 were found to have a high attack rate (Brueggemann et al. 2004). The major clone of serotype 4 belonged to ST205, internationally known as Sweden 4-38, named by the international network on antibiotic resistant pneumococci, PMEN. No type 4 isolate was found among carriers. One clone dominated among type 9V isolates, where four related MLST patterns were found, ST156, ST162, ST1184 and ST1185, all belonging to the same clonal cluster (i.e. differed in less than two out of seven alleles). 27

39 ST156 is an internationally recognised antibiotic resistant clone, PMEN clone Spain 9V - 3 (further discussed in paper IV). Serotype 6B and 14 were found both among invasive and carrier isolates, whereas serotype 6A and 19F were mainly found among carriers, and they all showed a high diversity in conducted molecular analyses. Serotype 19F was the most diverse type compared to all serotypes within the study. A total of 50 serotype 14 isolates were found, out of which 33 were acquired from patients with invasive disease. The major clone within serotype 14 was of ST124, also called Netherlands 14-35, a clone spreading successfully not only in Europe but also in countries on other continents, such as Australia and Canada. Henriques Normark et al observed an increased rate of IPD in Sweden during where this particular clone, seemed to be one major reason for the increase (Henriques Normark et al. 2001). Serotype 6A, 19F and 23F were more commonly found among carriers in our study and serotype 6B and 14 were common in both carriage and IPD, while serotype 3 mainly caused invasive disease. In contrast, serotype 3 was most commonly found causing carriage in the study by Bruggemanns et al (Brueggemann et al. 2004). However, the data from the different studies were, except for this, comparable and came to approximately the same conclusions. In Bruggemanns study the isolates were not characterised to serotype, only to serogroup, and no molecular characterisation was performed. The differences found might be explained by differences in clonal types between the studies, but may also be due to differences in host factors as well as differences in the collection of isolates with respect to geographical areas, ages and time periods studied. In conclusion, Serotype 1, 4, 7F and 9V were mainly found causing invasive disease, while type 6A, 6B, 14 and 19F were mainly found among carriers. Our data suggest that not only the capsular type itself, but also the clonal type is important for the invasive disease potential of pneumococci. Hence, also other bacterial factors than the capsule might be important for disease outcome. 4.2 PAPER II In the second project we aimed to investigate whether there are any correlations between clonal and/or capsular type with clinical characteristics such as age, underlying disease, disease severity and disease type. A total of 494 invasive isolates from adults, 18 years, collected from different parts of the world (Sweden, United States, Canada, 28

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