Efficacy of IntraVenous ImmunoGlobulins in Toxic Shock Syndromes: a Paediatric Pilot Study
Condition: Toxic Shock Syndrome
MeSH terms: Shock, Septic; Syndrome; Shock
Study type: Interventional
Phase: Phase 2

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.
    


Intervention name(s): Intravenous human immunoglobulin; Albumin
Intervention type(s): Drug; Drug
Intervention description(s): Single administration of IVIG 2 g/kg within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The bottles of IVIG used will contain 10 g of proteins in 100 ml of solution. Thus, to reach a concentration of 2 g/kg, will be administered 1 bottle per 5 kg of body weight (with a maximum of 14 bottles for 70 kg patients and over).; Single administration of albumin 4% within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The solution will be given at the same volume as IVIG (that is: 1 bottle / 5 kg of body weight).
Intervention MeSH terms: Immunoglobulins; Immunoglobulins, Intravenous; Antibodies
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Paediatrics; Toxic Shock Syndrome; Intravenous human immunoglobulin; feasibility