Efficacy of IntraVenous ImmunoGlobulins in Toxic Shock Syndromes: a Paediatric Pilot Study
Status:
Completed
Trial end date:
2019-04-19
Target enrollment:
Participant gender:
Summary
Staphylococcus aureus and Streptococcus pyogenes produce many virulence factors. Some of them
are responsible for severe infections in humans. Superantigen toxins synthesized by S. aureus
or by S. pyogenes, are responsible for toxic shock syndromes (TSS) which lethality can attain
25% in children with validated criteria of septic shock.
Previous studies, performed in vitro and in vivo in animals, have shown that Intravenous
immunoglobulins [IVIG] contain antibodies [Ab] against these toxins and, when used at high
concentration, IVIG are able to neutralize their toxicity. However, in all these studies,
IVIG administration has been preventive and there is no reliable data demonstrating their
therapeutic efficacy in vitro or in vivo in humans or in animals, once the disease is
present.
The efficacy of IVIG is established in other pathologies for which the role of the
superantigens [superAg] is suspected, like Kawasaki disease in children. The mechanism of
action, although not perfectly known, involves at the same time a direct effect on superAg
(Ag-Ab complex) and indirect effects like the neutralisation of superAg within the network of
anti-idiotype Ab or the neutralisation of the T-cells receptors. Staphylococcal and
streptococcal toxic shocks imply bacterial exotoxins that are superAg. It seems thus
consistent to imagine a same type of treatment with IVIG. However, there is currently no
evidence of the efficacy of IVIG in this indication. One of the explanations relies on the
lack of statistical power of previous adult studies, which principal objective was to show a
reduction of the mortality. Taking into account the low prevalence of TSS, it has been hard
to recruit enough patients to have the required statistical power. Moreover, some works have
been extracted from larger studies on septic shock and the definitions of the TSS were nor
always very reliable. Lastly, if the investigators consider the definition of the TSS as
mentioned by the " Centre for Disease Control " [CDC], for which any hypotension, even a
simple orthostatic hypotension, serves the diagnosis of TSS as long as the other symptoms are
present, it is obvious that many patients are likely to be recruited in a study although it
is highly probable that their health will get better with a " standard " treatment. The
definition of a " real " TSS can be refined, keeping the CDC criteria, but changing the
hypotension criterion in a more accurate criterion as described in the " surviving sepsis
campaign ", internationally accepted and based on norms adapted to the age for paediatric
forms.
IVIG therapy is very expensive and TSS is not recognized as indication of IVIG according to
their marketing authorization. The feasibility of a randomized controlled study with this
treatment needs to be assessed as it would be hazardous to conduct a large prospective RCT
without having first assessed this feasibility in terms of recruitment rates, consent rates
or compliance rates. Inclusion, randomisation and collect of inform consent in the context of
severe shock are challenging and require evaluation of feasibility. The sample size
calculation of the large study on mortality required estimations of the event in the specific
population of children with criteria of septic shock. Surrogates markers of outcome need to
be better defined. For example it would be useful to determine the evolution of organ
dysfunctions with and without IVIG treatment in this population.
Various organ failure scores, used upon admission and later on, have been validated in adults
and in children. The absence of improvement of the Paediatric logistic organ dysfunction
(Pelod) score over time is a good indicator of mortality in Paediatric intensive care unit
(PICU). It could be used as surrogate marker to evaluate the efficacy of IVIG.