[9] These early symptoms can include diarrhea (which is often bloody), stomach cramps, mild fever,[10] or vomiting that results in dehydration and reduced urine.
[11][12][13] People with HUS commonly exhibit the symptoms of thrombotic microangiopathy (TMA), which can include abdominal pain,[14] low platelet count,[15] elevated lactate dehydrogenase LDH, (an enzyme released from damaged cells, and which is therefore a marker of cellular damage)[16] decreased haptoglobin (indicative of the breakdown of red blood cells)[16] anemia (low red blood cell count), schistocytes (damaged red blood cells),[15][16] elevated creatinine (a protein waste product generated by muscle metabolism and eliminated renally),[17] proteinuria (indicative of kidney injury),[18] confusion,[14] fatigue,[19] swelling,[20] nausea/vomiting,[21] and diarrhea.
[22] Additionally, patients with aHUS typically present with an abrupt onset of systemic signs and symptoms such as acute kidney failure,[15] hypertension (high blood pressure),[19] myocardial infarction (heart attack),[23] stroke,[14] lung complications,[23] pancreatitis (inflammation of the pancreas),[21] liver necrosis (death of liver cells or tissue),[15][19] encephalopathy (brain dysfunction),[19] seizure,[24] and coma.
[25] Failure of neurologic, cardiac, renal, and gastrointestinal (GI) organs, as well as death, can occur unpredictably at any time, either very quickly or following prolonged symptomatic or asymptomatic disease progression.
[7][29][16] Despite the use of supportive care, an estimated 33–40% of patients will die or have end-stage renal disease (ESRD) with the first clinical manifestation of aHUS,[22][23] and 65% of patients will die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) therapy.
[22] Patients who survive the presenting signs and symptoms of aHUS endure a chronic thrombotic and inflammatory state, which puts them at lifelong elevated risk of sudden blood clotting, kidney failure, other severe complications and premature death.
[34] Shiga toxin enters the mesenteric microvasculature lining the intestines where it releases inflammatory cytokines including IL-6, IL-8, TNFα, and IL-1β.
[34] Once Shiga toxin enters the circulation it can travel throughout the body and cause the wide array of end organ damage and the multitude of symptoms seen with HUS.
Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis.
[11] The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, and are thus the most likely organs to be affected.
Other serotypes of STEC also cause disease, inlduding HUS, as occurred with E. coli O104:H4, which triggered a 2011 epidemic of STEC-HUS in Germany.
[25] Unlike typical HUS, aHUS does not follow STEC infection and is thought to result from one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement.
[40] Additionally, in one study, mutations of genes encoding several complement regulatory proteins were detected in 8 of 36 (22%) patients diagnosed with STEC-HUS.
[1][2] Early IV fluid hydration is associated with better outcomes including shorter hospital stays and reducing the risk of dialysis.
[34] Antidiarrheals and narcotic medications to slow the gut are not recommended as they are associated with worsening symptoms, increased risk of HUS in those with STEC infection, and adverse neurologic reactions.
Another 8% of persons with HUS have other lifelong complications, such as high blood pressure, seizures, blindness, paralysis, and the effects of having part of their colon removed.
[34] Patients with aHUS generally have poor outcomes, with up to 50% progressing to end-stage renal disease (ESRD) or irreversible brain damage; as many as 25% die during the acute phase.
Thrombotic thrombocytopenic purpura (TTP), a TMA, was first described by the Hungarian born, American pathologist and physician Eli Moschcowitz (1879–1964).
That was in a 16-year-old girl who died 2 weeks after the abrupt onset and progression of petechial bleeding, pallor, fever, paralysis, hematuria and coma; and called "Moschcowitz disease".
In the 1980s, Mohamed Karmali (1945–2016) was the first to make the association between Stx, diarrheal E. coli infection and the idiopathic hemolytic uremic syndrome of infancy and childhood.
He defined the presence of microvascular injury in diarrhea-associated HUS and the critical role of a verotoxin produced by specific strains of Escherichia coli.
[57] This relationship and the eventual link of TTP to abnormally high levels of ultra-large Von Willebrand factor (vWF) multimers caused by congenital or acquired reductions in ADAMTS13 activity was established at approximately the same time.
Paul Warwicker is an English nephrologist, whilst in Newcastle in the mid-1990s his research in molecular genetics with Professors Tim and Judith Goodship led to the genetic mapping of the familial form of atypical HUS and the descriptions of the first HUS-related mutations and polymorphisms in the factor H gene in both familial and sporadic HUS.
[58] Paul Warwicker confirmed the association of atypical HUS (aHUS) to defects in a region on chromosome 1 that contains the genes for several complement regulatory proteins.
These discoveries have allowed a more comprehensive understanding of the pathogenesis, evaluation, and treatment of the entire spectrum of TMA disorders and provide a more rational and effective approach to the care of these children with complicated disease.
Eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., Boston, MA, USA) is a humanized monoclonal complement inhibitor that is the first and only approved treatment for patients with aHUS by FDA in September 2011.
Eculizumab was proven to be effective in patients with aHUS in which it resolved and prevented complement-mediated TMA, improving renal function and hematologic outcomes.
"The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function," said Alexion R&D head John Orloff, M.D., who reckons the drug can become the "new standard of care for patients with aHUS."