Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
Abstract
Strepto coccus pyogenes , also known as group A streptococcus (GAS), is
an important human pathogen causing a wide variety of diseases. One of
the most severe diseases is streptococcal toxic shock syndrome (STSS),
which is associated with high mortality rates. Toxic shock syndrome (TSS)
may also be caused by Staphylococcus aureus. Superantigens have been
identified as key mediators of STSS and staphylococcal TSS. Intravenous
polyspecific immunglobulin (IVIG) has been suggested as adjunctive
therapy in TSS, since it contains neutralising antibodies against
streptococcal and staphylococcal superantigens, as well as bacterial
opsonising antibodies.
To assess the safety and efficacy of IVIG as adjunctive therapy in STSS,
we conducted a multicenter placebo-controlled trial (paper I). The trial
was prematurely terminated due to a low incidence of disease in the
participating countries. Results were obtained from 21 enrolled patients;
10 of whom received IVIG and 11 placebo. The primary objective was
mortality over 28 days, and a trend to decreased mortality was observed
in the IVIG group, 10% versus 36% in the placebo group. A significant
decrease in sepsis-related organ failure assessment (SOFA) score was
noted in the IVIG-group, whereas no change was seen in the placebo group.
The IVIG cases obtained a significantly increased plasma
superantigen-neutralising activity against their own isolate following
IVIG administration, whereas no change could be noted among patients in
the placebo group.
In paper II we tested whether superantigen-containing culture
supernatants from streptococcal and staphylococcal severe sepsis isolates
were inhibited to an equal extent by IVIG. Three different IVIG
preparations were tested and found to be highly efficient in neutralising
the superantigens. Most supernatants were completely inhibited at
concentrations between 0.5 - 2.5 mg IVIG/ml. Importantly, culture
supernatants from S. pyogenes isolates were consistently inhibited to a
higher extent as compared to those of S. aureus isolates.
In paper III and IV, results from active surveillance of invasive GAS
infections in Denmark and Sweden during 2001-02 and 2002-04,
respectively, are described. The yearly incidences were similar, 2.0-3.4
/100 0000 inhabitants, as was the prevalence of the severe manifestations
STSS and necrotising fasciitis (NF), which were seen in approximately 10%
of the cases. However, differences were observed in outcome with a
mortality rate of 25% and 14.5% in Denmark and Sweden, respectively. Also
the GAS type distribution varied between the two studies. emm1 was the
most prevalent type (32%) in the Danish study in comparison to the new
types emm89 (16%) and 81 (14%) that dominated in the Swedish study.
Non-invasive GAS isolates were collected and analysed in parallel with
the invasive in both studies, and the type distribution differed
significantly from the invasive isolates. Differences in presence of
superantigen genes were seen between isolates of different emm-types and
also between invasive and non-invasive isolates. A combination of
PFGE-analysis and superantigen profiling revealed subclones within the
emm-types with higher invasiveness than others (paper IV). Further, IVIG
treatment in patients with STSS was significantly associated with
improved outcome. 20 out of 72 patients with STSS were given IVIG, with a
mortality of 15% as compared to 48% among patients not receiving IVIG
(paper IV)
This thesis provides further support of IVIG therapy in STSS, and the in
vitro analyses revealed that a higher dose of IVIG may be needed in
staphylococcal TSS in order to achieve protective antibody levels. The
thesis also provides new insights in the molecular epidemiology of
invasive GAS disease