Azithromycin in Post Diarrheal Haemolytic and Uremic Syndrome
Status:
Completed
Trial end date:
2021-04-01
Target enrollment:
Participant gender:
Summary
Post diarrheal hemolytic and uremic syndrome (D+HUS) is the first etiology of acute renal
failure in children less than 5 years old in France. Previous works highlighted a mortality
rate of 2 % and a prevalence of renal sequelae at one year after D+HUS onset in 25 % of
patients D+HUS is a consequence of a gastrointestinal infection with shiga toxin (Stx)
producing E.coli (STEC). The most frequent straight is E.coli O157H7. The sequence of STEC
induced HUS is now well known. Typically, digestive symptoms appear five days following STEC
ingestion. STEC colonize the intestinal mucosa, adhere to the enterocyte and cause a typical
attaching/effacing lesion and inflammation. Then, diarrhea and vomiting occurred. D+HUS
occurs in about 10% of patients and is a consequence of Stx systemic absorption. Indeed, Stx
are released in the gastrointestinal tract, then after transferred to the systemic
circulation. At the cellular level, Stx binds the globotriosylceramide (Gb3Cer) localized at
the surface of the endothelial and epithelial cells of target organs. Following binding to
Gb3Cer, the A subunits of Stx are internalized and trigger the activation of the apoptotic
program leading to cell death. In addition, Stx are also able to enhance the production and
the release of pro inflammatory factor (IL-1, TNFα, IL-6). Cytokines locally produced by
Stx-stimulated cells can amplify the inflammatory processes and the prothrombotic state
leading to the constitution of the microangiopathic lesions of HUS. To this day, management
of D+HUS involves supportive care mainly based on fluid management, dialysis and red blood
cells transfusions. Specific therapies used in D+HUS (plasma infusion, antithrombotic and
anti inflammatory agents) failed to improve the course of D+HUS. The use of antibiotics
remains not recommended while meta-analysis clearly showed that the use of bactericidal
antibiotics could worse the course of D+HUS. In vitro experimentations highlighted that some
classes of antibiotics like fluoroquinolones dramatically increase the production and the
release of Stx before bacterial lysis and worsen the outcome of D+HUS in animal models. By
contrast, azythromycin, a bacteriostatic antibiotic of the macrolides family blocking the
protein synthesis in bacteria, has a strong inhibitory effect on Stx production and release
by STEC as well as it inhibits the in vitro growth of STEC strains. In addition, azithromycin
is able to inhibit the Stx-induced production of inflammatory cytokines which are considered
to be essential for the development of D+HUS. Consistently the use of azithromycin in animal
models of D+HUS dramatically improved the survival rate. Preliminary data on humans with
D+HUS treated with azithromycin highlighted a lower prevalence of severe gastrointestinal
involvement than in control patients. All these data supported the hypothesis that
azithromycin should have a beneficial effect on D+HUS and should improve the short and long
term outcome and deserves to be formally demonstrated in human with D+HUS.