Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children
The hemolytic uremic syndrome (HUS) is characterized by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most common cause of HUS is Shiga toxin-producing Escherichia coli (STEC), which accounts for 90 percent of pediatric cases of HUS. (See 'Epidemiology' above.)
●STEC HUS primarily follows an infection with STEC. The most common serotype in the United States is O157:H7, which is found in 70 percent of cases, but other serotypes have been reported. (See 'Microbiology'above.)
●Children with STEC HUS typically have a prodromal illness with abdominal pain, vomiting, and diarrhea (usually bloody) that immediately precedes the development of HUS (figure 1). Five to 10 days after the onset of diarrhea, HUS presents suddenly with the following classical findings (see 'Clinical and laboratory manifestations' above):
•Microangiopathic hemolytic anemia – Hemoglobin levels are usually less than 8 g/dL. The Coombs' test is negative and the peripheral blood smear is characterized by the large number of schistocytes and helmet cells (picture 1 and picture 2). There is no correlation between the severity of the anemia and the severity of the renal disease.
•Thrombocytopenia – Platelet counts are generally around 40,000/mm3. There is no correlation between the degree of thrombocytopenia and the severity of the kidney disease.
•Acute kidney injury – The severity of kidney involvement ranges from hematuria and proteinuria to severe kidney failure and oligoanuria, which occur in one-half of cases. Hypertension is also frequently observed. Although as many as 50 percent of those with HUS require dialysis during the acute phase, the prognosis for recovery of kidney function is generally favorable.
●STEC HUS may also involve other organ systems including the central nervous system (CNS), gastrointestinal tract, pancreas, and liver. Severe CNS involvement (eg, seizures, coma, and stroke) is associated with significant mortality. (See 'Clinical and laboratory manifestations' above.)
●A patient with a recent history of diarrhea (possibly bloody) who presents with symptoms and signs of a multisystem disorder requires a quick and accurate assessment for hemolytic uremic syndrome (HUS). The evaluation includes a complete blood count, kidney function studies (eg, serum creatinine level), review of the peripheral smear to determine whether there are findings consistent with microangiopathic hemolysis (eg, schistocytes and helmet cells (picture 1 and picture 2)), and screening for Shiga toxin-producing bacteria. (See 'Evaluation' above.)
●The diagnosis of STEC HUS in children is generally made on clinical grounds from the characteristic clinical and laboratory findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury following a diarrheal prodrome due to STEC. The demonstration of Shiga toxin exposure relies on one of the following: positive stool culture, detection of Shiga toxin genes in stools by polymerase chain reaction (PCR), or the presence of serum IgM antibodies against lipopolysaccharides of major enterohemorrhagic E. coli. (See 'Diagnosis' above.)
●The differential for STEC HUS includes other enteric infections, disseminated intravascular coagulation, and non-STEC HUS. (See 'Differential diagnosis' above.)
Progression of E coli O157:H7 infections in children
About three days after ingestion of the organism, the patient develops diarrhea, abdominal pain, fever, and vomiting. The diarrhea becomes bloody one to three days later, rarely on the first day. In 80 to 90 percent of infected children with positive cultures, visible blood is present in the stools. When bloody diarrhea first develops, the patient has a normal platelet count, creatinine concentration, and packed-cell volume, with no red-cell fragmentation. However, if studies of the coagulation and fibrinolytic systems are done early in the illness, there is evidence that thrombin generation is increased, fibrin deposition is occurring, and plasminogen activation is suppressed.
HUS: hemolytic uremic syndrome.
Reproduced with permission from: Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coliand haemolytic uraemic syndrome. Lancet 2005; 365:1073. Copyright ©2005 Elsevier.
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Peripheral smear in microangiopathic hemolytic anemia showing presence of schistocytes
Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with marked red cell fragmentation. The smear shows multiple helmet cells (arrows), other fragmented red cells (small arrowhead); microspherocytes are also seen (large arrowheads). The platelet number is reduced; the large platelet in the center (dashed arrow) suggests that the thrombocytopenia is due to enhanced destruction.
Courtesy of Carola von Kapff, SH (ASCP).
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Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several platelets (arrows) and a normal lymphocyte (arrowhead) can also be seen. The red cells are of relatively uniform size and shape. The diameter of the normal red cell should approximate that of the nucleus of the small lymphocyte; central pallor (dashed arrow) should equal one-third of its diameter.
Courtesy of Carola von Kapff, SH (ASCP).
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Helmet cells in microangiopathic hemolytic anemia
Peripheral smears from two patients with microangiopathic hemolytic anemia, showing a number of red cell fragments (ie, schistocytes), some of which take the form of combat (red arrow), bicycle (thick black arrow), or football (blue arrow) "helmets." Microspherocytes are also seen (thin black arrows), along with a nucleated red cell (green arrow).
Courtesy of Carola von Kapff, SH (ASCP).
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Light micrograph showing renal thrombotic microangiopathy with intracapillary glomerular thrombi
Light micrograph showing multiple intracapillary glomerular thrombi (arrows) typical of a thrombotic microangiopathy as can be seen in any of the forms of the hemolytic uremic syndrome.
Courtesy of Helmut Rennke, MD.
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Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
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Light microscopy showing thrombotic microangiopathy with subintimal fibrin deposition in an interlobular artery
Subintimal fibrin deposition without inflammation (arrow) in an interlobular artery as can be seen acutely in any of the forms of the hemolytic uremic syndrome, including scleroderma. The marked narrowing of the vascular lumen will diminish distal perfusion, potentially leading to tissue necrosis if there is near total or total occlusion.
Courtesy of Helmut Rennke, MD.
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Light microscopy showing thrombotic microangiopathy with mucoid intimal thickening of a muscular renal artery
Mucoid intimal thickening of muscular renal arteries (arrows) as an early healing response to previous fibrinoid injury in any of the forms of the hemolytic uremic syndrome, including scleroderma and malignant hypertension.
Courtesy of Helmut Rennke, MD.
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Light microscopy showing thrombotic microangiopathy with onion-skin thickening of a muscular renal artery
Concentric onion-skin thickening of a muscular renal artery, leading to complete obliteration of the vascular lumen, during the later healing phase of previous fibrinoid injury in any of the forms of the hemolytic uremic syndrome, including scleroderma and acute hypertensive nephrosclerosis (formerly called "malignant nephrosclerosis").
Courtesy of Carol Black, MD.
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Immunofluorescence microscopy showing fibrin deposition in thrombotic microangiopathy
Immunofluorescence microscopy in the hemolytic uremic syndrome shows fibrin deposition (bright yellow areas) in branches of a muscular renal artery.
Courtesy of Helmut Rennke, MD.
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Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children
Therapy for STEC-HUS is supportive and includes the following (see 'Supportive therapy' above):
●Patients with HUS can become profoundly and rapidly anemic and require red blood cell transfusions. In our clinical experience, we transfuse when the hemoglobin level falls below 6 g/dL. (See 'Anemia' above.)
●We suggest platelet transfusion only if there is active bleeding or prior to a required invasive procedure in patients with platelet counts less than 30,000/mm3 (Grade 2C). (See 'Thrombocytopenia' above.)
●For each patient, the fluid status is assessed and management is directed toward returning the patient to a euvolemic state. In particular, management should be directed to rapidly correct any evidence of volume depletion. Fluids are then administered as insensible losses plus urine output until renal function returns to normal. Frequent monitoring of fluid balance, weight, and vital signs is required to detect early signs of fluid overload. If this occurs, prompt fluid restriction is begun. (See 'Fluid management' above.)
●Initial assessment and monitoring are required to detect hyperkalemia, hyperphosphatemia, and metabolic acidosis. Management of these disorders is the same as in patients with other causes of AKI. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Electrolyte management'.)
●Dialysis therapy is initiated as indicated for AKI. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Renal replacement therapy' and "Pediatric acute kidney injury: Indications, timing, and choice of modality for renal replacement therapy (RRT)".)
●Hypertension is managed by fluid restriction, antihypertensive agents, and dialysis if needed. We suggest the use of calcium channel blockers (such as nifedipine or nicardipine) as the initial choice of antihypertensive agents in the acute phase of the illness (Grade 2C). (See 'Hypertension' above.)
●Parenteral antiepileptic agents (eg, diazepam, phenytoin, and fos-phenytoin) are used in the management of seizures in patients with HUS. (See "Management of convulsive status epilepticus in children".)
●In patients with severe neurologic involvement, we suggest administering eculizumab, a monoclonal antibody to complement factor C5 that blocks complement activation (Grade 2C). (See 'Eculizumab' above.)
●We do not recommend the use of antithrombotic agents or oral Shiga toxin-binding agent (Grade 1B). (See 'Specific therapy' above.)
Prognosis and follow-up
●In general, the short-term prognosis is favorable with mortality rates below 5 percent. However, the risk of renal failure 20 years after recovery is not negligible and long-term follow-up is recommended. In patients who require renal transplantation, recurrence of HUS is rare. (See 'Prognosis' above.)
●Yearly evaluations of patients with HUS include blood pressure measurement, urinalysis, and serum creatinine. (See 'Follow-up' above.)
●After the acute phase of HUS, we suggest that angiotensin converting enzyme (ACE) inhibitors be given in patients who have renal sequelae (Grade 2C). (See 'Hypertension' above.)
Antihypertensive drugs for outpatient management of hypertension in children 1 to 17 years old
| Class | Drug | Dose* | Dosing interval | Comments¶ |
| ACE inhibitor | Benazepril | Initial: 0.2 mg/kg per day up to 10 mg/day | Once daily |
|
| Maximum: 0.6 mg/kg per day up to 40 mg/day | ||||
| Captopril | Initial: 0.3 to 0.5 mg/kg per dose | Three times daily | ||
| Maximum: 6 mg/kg per day | ||||
| Enalapril | Initial: 0.08 mg/kg per day up to 5 mg/day | Once to twice daily | ||
| Maximum: 0.6 mg/kg per day up to 40 mg/day | ||||
| Fosinopril |
Children >50 kg:
Initial: 5 to 10 mg/day
Maximum: 40 mg/day | Once daily | ||
| Lisinopril | Initial: 0.07 mg/kg per day up to 5 mg/day | Once daily | ||
| Maximum: 0.6 mg/kg per day up to 40 mg/day | ||||
| Quinapril | Initial: 5 to 10 mg/day | Once daily | ||
| Maximum: 80 mg/day | ||||
| Angiotensin-receptor blocker | Irbesartan | 6 to 12 years: 75 to 150 mg/day | Once daily |
|
| ≥13 years: 150 to 300 mg/day | ||||
| Losartan | Initial: 0.7 mg/kg per day up to 50 mg/day | Once daily | ||
| Maximum: 1.4 mg/kg per day up to 100 mg/day | ||||
| Alpha- and beta-blocker | Labetalol | Initial: 1 to 3 mg/kg per day | Twice daily |
|
| Maximum: 10 to 12 mg/kg per day up to 1200 mg/day | ||||
| Beta-blocker | Atenolol | Initial: 0.5 to 1 mg/kg per day | Once to twice daily |
|
| Maximum: 2 mg/kg per day up to 100 mg/day | ||||
| Bisoprolol/HCTZ | Initial: 2.5/6.25 mg/day | Once daily | ||
| Maximum: 10/6.25 mg/day | ||||
| Metoprolol | Initial: 1 to 2 mg/kg per day | Twice daily | ||
| Maximum: 6 mg/kg per day up to 200 mg/day | ||||
| Propranolol | Initial: 1 to 2 mg/kg per day | Two to three times daily | ||
| Maximum: 4 mg/kg per day up to 640 mg/day | ||||
| Calcium channel blocker | Amlodipine | Children 6 to 17 years: 2.5 to 5 mg once daily | Once daily |
|
| Felodipine | Initial: 2.5 mg/day | Once daily | ||
| Maximum: 10 mg/day | ||||
| Isradipine | Initial: 0.15 to 0.2 mg/kg per day | Three to four times daily (immediate release formulation) | ||
| Maximum: 0.8 mg/kg per day up to 20 mg/day | ||||
| Extended-release nifedipine | Initial: 0.25 to 0.5 mg/kg per day | Once to twice daily | ||
| Maximum: 3 mg/kg per day up to 120 mg/day | ||||
| Central alpha-agonist | Clonidine |
Children ≥12 years:
Initial: 0.2 mg/day
Maximum: 2.4 mg/day | Twice daily |
|
| Diuretic | HCTZ | Initial: 1 mg/kg per day | Once daily |
|
| Maximum: 3 mg/kg per day up to 50 mg/day | ||||
| Chlorthalidone | Initial: 0.3 mg/kg per day | Once daily | ||
| Maximum: 2 mg/kg per day up to 50 mg/day | ||||
| Furosemide | Initial: 0.5 to 2 mg/kg per dose | Once to twice daily | ||
| Maximum: 6 mg/kg per day | ||||
| Spironolactone | Initial: 1 mg/kg per day | Once to twice daily | ||
| Maximum: 3.3 mg/kg per day up to 100 mg/day | ||||
| Triamterene | Initial: 1 to 2 mg/kg per day | Twice daily | ||
| Maximum: 3 to 4 mg/kg per day up to 300 mg/day | ||||
| Amiloride | Initial: 0.4 to 0.625 mg/kg per day | Once daily | ||
| Maximum: 20 mg/day | ||||
| Alpha 1-antagonist | Doxazosin | Initial: 1 mg/day | Once daily | May cause hypotension and syncope, especially after first dose. |
| Maximum: 4 mg/day | ||||
| Prazosin | Initial: 0.05 to 0.1 mg/kg per day | Three times daily | ||
| Maximum: 0.5 mg/kg per day | ||||
| Terazosin | Initial: 1 mg/day | Once daily | ||
| Maximum: 20 mg/day | ||||
| Vasodilator | Hydralazine | Initial: 0.75 mg/kg per day | Four times daily |
|
| Maximum: 7.5 mg/kg per day up to 200 mg/day | ||||
| Minoxidil |
Children <12 years:
Initial: 0.2 mg/kg per day
Maximum: 50 mg/day | One to three times daily | ||
Children ≥12 years:
Initial: 5 mg/day
Maximum: 100 mg/day |
ACE inhibitor: angiotensin converting enzyme inhibitor; FDA: US Food & Drug Administration; ARB: angiotensin-receptor blocker; HCTZ: hydrochlorothiazide.
* The maximum recommended adult dose should not be exceeded in routine clinical practice.
¶ Comments apply to all members of each drug class except where otherwise stated. Includes drugs with prior pediatric experience or recently completed clinical trials.
* The maximum recommended adult dose should not be exceeded in routine clinical practice.
¶ Comments apply to all members of each drug class except where otherwise stated. Includes drugs with prior pediatric experience or recently completed clinical trials.
Data from: National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114 (2 Suppl 4th Report):555.
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