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Anusual presentation of typical HUS in childhood: a case study

Barbalace A1, Dipasquale V 1, Conti G 2, Fede C 2
1 Department of Pediatrics, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
2 Department of Pediatrics, Pediatric Nephrology and Rheumatology with Dialysis Unit, , University of Messina, Messina, Italy

Hemolytic Uremic Syndrome (HUS) is a rare condition traditionally defined by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, that usually occurs within a week after prodromal hemorrhagic enterocolitis. It is traditionally classified into typical, mostly caused by Shiga toxin-producing Escherichia coli, and atypical, associated with genetic or acquired disorders of regulatory components of the complement system. Severe cases can also be presented by acute respiratory distress syndrome (ARDS), toxic megacolon with ileus, pancreatitis, central nervous system (CNS) disorders and multiple organ failure (MOF) . 70% of children with HUS recover without permanent health consequences, 2–5% of patients die in the acute phase. In this case report, we present a child with typical HUS that had an unusual presentation and good outcome by an exclusively conservative treatment.

Case report
A previously healthy 19 month-old Caucasian girl was admitted to AOU G. Martino Hospital of Messina for the occasional detection of proteinuria (2 +) and hematuria (3 +), without any signs or symptoms. Her laboratory findings were: hemoglobin (Hb) 9.8 gr%, hematocrit (Hct) 28%, platelet count 166.000 mmc, white blood cell (WBC) count 8.190 mmc, lactate dehydrogenase (LDH) 810 U/L, albumins 36 g/L, total blood proteins 5.3 g/dL. Renal ultrasonography, performed in the following days, only highlighted a bilateral hyperechogenicity as a nonspecific sign of kidney inflammation. Glomerulopathy was initially suspected. Additional laboratory tests (antistreptolysin O titre, complement C3 and C4 levels, serum immunoglobulin) ruled out glomerulonephritis and pointed out laboratory signs of vascular microangiopathy and of the intravascular microangiopathic nature of hemolysis (presence of fragmented erythrocytes in circulation – schistocytes -, negative Coombs test, decreased serum levels of haptoglobin and increased serum levels of LDH and reticulocytes) Such data in association with the medical history of diarrhea in the days prior to admission suggest a HUS with mild course without impaired renal function. It was confirmed by the results of the analysis carried out on stool and blood samples previously sent to the Superior Health Institute which revealed an Entherohemorragic EC O111 strain at the coprological exam and anti- lipopolysaccharide antibodies to E. coli O111 in the blood. A typical HUS caused by reaction to E. coli toxin was diagnosed. In the following days the girl underwent to a progressive spontaneous normalization of proteinuria and a reduction of microscopic hematuria without any specific therapy except for a supportive one (fluid therapy) and close clinical observation for the acute phase, which resolved in about 10 days. The next follow-up controls confirmed the progressive and complete resolution of the clinical framework, with progressive restore of anemia, thrombocytopenia and normalization of LDH and haptoglobin blood values.
Hemolytic-uremic syndrome (HUS) is defined by the simultaneous presence of acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia and represents a leading cause of acute renal failure in infants and young children (1) . HUS is traditionally classified into typical (with diarrhea) and atypical (no diarrhea), according to its etiology (2) . Typical HUS results from Shiga toxin-producing Escherichia Coli (STEC) infection, or less commonly Shigella Dysenteriae type 1 infection. (3) It is the most common type with an overall incidence of 2.1 per 100 000 people and a peak incidence in children younger than 5 years (6.1 per 100 000) . (2) All HUS cases due to other etiologies are classified as atypical HUS, which includes 5% to 10% of all cases of HUS in children. (3) Clinical manifestations of HUS are the consequence of severe systemic inflammation and immune reactions that lead to thrombotic microangiopathy in susceptible organs. In typical HUS, those reactions are initiated by binding of Shiga toxin (STX), also known as Verotoxin (VT), to the endothelial membrane-bound Gb3 receptor and subsequent activation of platelets and leukocytes (4) ; in atypical HUS, those reactions are mediated by excessive activation of complement (1) .


Figure 1.
Characteristic features of the typical form of the syndrome are hemorrhagic enterocolitis, hemolytic anemia, thrombocytopenia and acute renal failure, but some patients develop more unusual manifestations that potentially lead to MOF and increase mortality. (5)
Atypical HUS usually presents abruptly with pallor, anorexia, vomiting, edema, hypertension, and oliguria. Patients with HUS can have extra-renal sequelae: sequelae of digestive system (cholelithiasis, persistent pancreatitis and colon stricture) (6, 7), diabetes mellitus (8), neurological complications (including epilepsy, hemiplegia, cortical blindness and psychomotor disturbance) (9, 10) , behavioral and cognitive sequelae (11, 12) or cardiovascular sequelae, such as myocarditis, cardiac thrombotic microangiopathy, dilated cardiomyopathy (13, 23), cardiac tamponade (24) and ischemic myocardial involvement. (25) The central nervous system symptoms are the most common extrarenal manifestation of atypical HUS, appearing as irritability, drowsiness, seizure, cortical blindness, hemiparesis, or coma. (14) In 20% of patients atypical HUS could present gradually with mild symptoms. (15) It has poorer prognosis with a tendency to relapse within a few months after remission. (15, 16) In a recent report from India, atypical HUS in older children had a relapse rate of 80.5% in 70 days. (17) In case of typical HUS the diagnosis of STEC infection can be suggested by the presence of STX in stool, serum antibody against E. coli O antigen or anti STX antibody in serum. The presence of STX is the most reliable marker of STEC. (16) The most common serotype of Shiga toxin producing Escherichia Coli (STEC) isolated from HUS patients was O157. For patients who are O157 negative, O121, O111, O26, and O145 are identified (17) . The mainstay of treatment is supportive. It includes control of fluid and electrolyte balance through intravenous fluid therapy using isotonic solutions, which should be used for patients with Shiga toxin-producing E. Coli (STEC) infection before the development of HUS or in its early stage for preventing oliguria, anuria and dialysis (18, 19) ; enteral and parenteral nutrition, hemodialysis (required in two-thirds of patients) (20), control of hemodynamic stability and transfusion of blood derivatives can be useful. Plasmapheresis with fresh frozen plasma is reserved for the most severe cases, (21) although it was proven ineffective in some recent controlled clinical trials. (22) Platelet transfusion is usually not recommended considering some studies have suggested it could exacerbate thrombogenesis and worsen outcome. (5) However, in cases of severe bleeding tendency or massive bleeding, platelet transfusion is required. Use of antibiotics is controversial and should be avoided, since some studies have shown them to be possible triggers for the development of HUS in patients with enterohemorrhagic E. coli infection. (2) Eculizumab is a recombinant monoclonal humanized IgG antibody that has been used for patients with STEC-associated HUS to suppress activated complement system, particularly effective in childhood cases (21) and in cases of failure of plasma exchange in atypical HUS. 70% of children with HUS recover without permanent health consequences, 2–5% of patients die in the acute phase. (2, 20)
This case report shows that typical hemolytic uremic syndrome could have unusual presentations such as the absence of oliguria, hypertension, and edema, with rapid recovery and good prognosis. The child has needed only supportive treatment (intravenous fluid therapy) and close clinical observation for the acute phase which went on without the appearance of the most feared complications of HUS (severe renal failure requiring dialysis, MOF, involvement of the central nervous system, bowel perforation) . The first-line therapy of choice is the meticulous supportive treatment through aggressive fluid therapy in many cases of HUS, above all in the early stage, in order to prevent oliguria, anuria and dialysis, as in the case of our patient. Monitoring of prognostic factors is important for early performance of appropriate diagnostic and therapeutical interventions.


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