pediatric hemolytic uremic syndrome
Introduction
Introduction to hemolytic uremic syndrome in children Hemolyticuremic syndrome (HUS) is a clinical syndrome involving multiple systems, characterized by microvascular hemolysis, acute renal failure and thrombocytopenia. It is one of the common causes of acute renal failure in children. Children with HUS above /3 may have neurological involvement. Because HUS and thrombocytopenic purpura (TTP) have similarities in etiology, pathogenesis and clinical manifestations, more and more scholars believe that the two are clinical manifestations of different stages of the same disease, collectively It is HUS/TTP or thrombotic microangiopathy (TMA). Histopathological injury in HUS is a thrombotic microangiopathy. Many functional and pathological changes are the result of endothelial cell damage, and kidney involvement is the most severe. Children are more common than adults. With the improvement of diagnosis and treatment technology, the prognosis of HUS has changed. basic knowledge Sickness ratio: 0.0002%-0.0005% Susceptible people: children Mode of infection: non-infectious Complications: acute renal failure, children with hypochloridemia, metabolic acidosis, congestive heart failure
Cause
Causes of hemolytic uremic syndrome in children
(1) Causes of the disease
It is not clear that the following exogenous or endogenous factors may be involved in the pathogenesis of HUS.
1. Classification With the deepening of the understanding of this disease, the current accepted types are as follows:
(1) HUS (post-diarrheal, D+HUS) after diarrhea: about 90% of all HUS, also known as typical performance, there is a small epidemic, but also scattered, diarrhea often accompanied by bloody stool, and Shiga toxoid (Shiga- Like toxin, SLT) is related to bacteria, and most of them are caused by Escherichia coli 0157:H7 (E.0157:H7).
(2) Non-diarrheal HUS (D-HUS): About 10% of cases, also known as atypical seizures, are divided into:
1 Secondary HUS: This disease is rare in children. Fitzpatrik in the United Kingdom reported that 192 cases of HUS had D-HUS in 23 cases, accounting for 12%; in a group of 226 cases of HUS in Canada, only D-HUS in 12 cases accounted for 5.3%. The most common cause of infection is streptococcal pneumonia or sepsis, followed by beta-hemolytic streptococcus, mycoplasma infection, primary and secondary glomerular lesions (such as SLE), drugs (such as cocaine, quinine, silk mold) , cyclosporine, FK-506, etc.), bone marrow transplantation, tumor, collagen vascular disease, AIDS, etc., no seasonal differences, often with prodromal symptoms.
2 idiopathic HUS: the cause is unknown, mostly sporadic, often genetic family tendency, no exact pre-infection, no autosomal dominant or recessive inheritance, high mortality, and development of ESRD Common, recurrence accounts for about 20%.
2. Causes
(1) Infection: It is the primary factor in inducing HUS in children. Bacterial infections such as Escherichia coli, Shigella dysenteriae, Streptococcus pneumoniae and Salmonella and viral infections, including Coxsackie virus, Echovirus, influenza virus, human Immunodeficiency virus (HIV) can induce HUS. It has been shown that hemorrhagic Escherichia coli (EHEC) 0157:H7 is the main pathogen of HUS related to epidemic diarrhea in some areas. 0157:H7 is mainly found in livestock. Intestinal, uncooked meat and unsterilized milk, up to 53% of children with EHEC 0157:H7 infections develop HUS.
(2) drugs: anti-tumor drugs such as vincristine, mitomycin, 5-fluorouracil, cisplatin are more common, and immunosuppressive agents such as cyclosporine can also induce HUS.
(3) Organ transplantation: HUS can occur after bone marrow transplantation and kidney transplantation, the incidence rate is 3.4% and 6% to 9% respectively. Once the HUS occurs after bone marrow transplantation, the prognosis is dangerous, and may be combined with high-dose chemotherapy, radiotherapy, and rejection. Reaction, infection, etc.
(4) Immunodeficiency diseases: such as congenital agammaglobulinemia and thymus-free lymphocytosis.
(5) Genetic factors: HUS can occur in the same family of siblings. It is currently considered that HUS is autosomal recessive, occasionally dominant, and the prognosis of familial HUS is poor, with a mortality rate of 68%.
(6) Others: Some autoimmune-related diseases such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome and malignant tumors can cause HUS, which is more common in adults.
(two) pathogenesis
1. Pathogenesis The pathogenesis of HUS is not known. The pathogenesis of HUS caused by different pathogenic factors is different, but capillary endothelial cell injury is its common pathogenic pathway. The damaged endothelial cells initiate the coagulation system, causing platelets to Local aggregation, thrombosis and fibrin deposition cause red blood cells and platelets to be destroyed by mechanical damage, causing microvascular thrombosis, hemolytic anemia and thrombocytopenia; in the kidney, microvascular thrombosis causes intrarenal circulatory disorders, and then acute Renal failure, recent studies have suggested that the pathogenesis of HUS involves the following aspects:
(1) endotoxin-induced endothelial cell damage: EHEC produces endotoxin in the intestinal tract. There are two main types: one is Shigalike toxin (SLTs), also known as verotoxin (VTs), which can be combined. On the surface of endothelial cells, globotriaosylceramide (CB3) is decomposed into A chain and B chain after phagocytosis into cytoplasm. A chain can cleave adenine of ribosomal transfer RNA, causing cell damage caused by protein synthesis. Or death; SLTs still induce renal cell apoptosis, apoptosis plays a role in the pathogenesis of HUS, and the number of apoptotic cells is related to disease severity, and the other is bacterial lipopolysaccharide (LPS). LPS damages endothelial cells by up-regulating plasminogen activator inhibitor (PAI) and down-regulating thrombomodulin expression, and promotes thrombosis. LPS can also promote adhesion of leukocytes and platelets to endothelial cells.
(2) Cytokine effects: Many cytokines are involved in the pathogenesis of HUS, tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, IL-1 and other release increases, TNF can induce Epithelial cell procoagulant activity and GB3 receptor expression; IL-6 is a marker of disease activity, related to disease severity and prognosis; IL-8 is a leukocyte activator that releases elastase after leukocyte activation Increased adhesion to endothelial cells, involved in the onset and aggravated lesions.
(3) Prostacyclin (PGI2) and thromboxane A2 (thromboxane, TXA2) imbalance: normal endothelial cells can synthesize PGI2, have dilated blood vessels and inhibit platelet aggregation, and maintain dynamic balance with TXA2, which promotes platelet aggregation. Patients with low PGI2 may be associated with the onset of the disease. It is speculated that the diseased children lack some kind of plasma factor that produces PGI2 or PGI2 synthetase inhibitor. It is possible that HUS patients will accelerate the degradation of PGI2.
(4) Coagulation and fibrinolysis system abnormalities: platelet-aggregating substances such as platelet activating factor (PAF), abnormal macromolecular von Willebrand factor (vWF) multimers, etc.; platelet release products such as -thromboglobulin ( Increased -TG); endothelial cells release tissue factor, activate coagulation system, microthrombus is extensively formed; fibrinolysis is destroyed, D-dimer and PAI are decreased.
(5) Others: Some scholars have noted that endothelin-nitric oxide axis and immune dysfunction may also play a role in the pathogenesis of HUS.
2. Pathological changes Renal pathological changes were characterized by intravascular platelet aggregation with cellulose deposition and microthrombus formation.
(1) glomerular type: more common in children, glomerular capillary endothelial cells swelling, shedding, intermittent widening under the endothelial cells, mesangial cell insertion phenomenon, glomerular capillary lumen stenosis, microthrombus formation and Segmental fibrinous necrosis.
(2) vascular type: mainly into the small arteries, interlobular and arcuate branches, visible arterial intima edema, cellulose necrosis, intravascular thrombosis, thrombosis, endothelium-like hyperplasia.
(3) Cortical necrosis: It is a large, renal artery thrombosis and occlusion. Immunofluorescence shows fibrinogen deposition in the glomerulus. Sometimes IgM and C3 are deposited on the glomerular capillary wall.
Prevention
Pediatric hemolytic uremic syndrome prevention
The cause is still unclear. At present, the focus should be on prevention and treatment of various infectious diseases. The HUS associated with diarrhea is Shiga toxin, which is mainly related to Escherichia coli O157 infection. It should be actively controlled. HUS occurs after pre-infection. Premonition factors:
1. Signs of HUS: CRP>1.2mm/dl, white blood cells>11.0×109/L, body temperature>38°C, these three indicators are considered to be the predictors of HUS after E. coli infection.
2. Risk factors for HUS: Bell et al believe that the application of antibiotics (braking agent) for the first 3 days of the disease, age <5.5 years, severe vomiting, white blood cells>13×109/L, the risk of HUS is 7-8 higher than the control group. Times.
3. High-risk parameters of D+HUS occur: After bacterial infection of gastroenteritis, low levels of neopterin and high levels of IL8 and particularly low levels of IL10 are high-risk parameters for D+HUS.
4. Others: Foreign scholars believe that if there is low acyl sphingosine trihexoseemia, there is a high incidence of HUS after VTEC infection.
5. Protection gene of HUS: Shimazu et al reported that the expression of B antigen has a protective effect on the pathogenesis of HUS.
The above is for us to make reference in clinical prevention work.
Complication
Complications of hemolytic uremic syndrome in children Complications acute renal failure children hypochlorremia azotemia syndrome metabolic acidosis congestive heart failure
Concomitant hemolytic crisis, bleeding tendency, acute renal failure, may have azotemia, metabolic acidosis, hyperkalemia, etc., can cause congestive heart failure, nervous system involvement, some may have neurological sequelae, intelligence Low or epilepsy, cardiovascular system damage manifested as hypertension, arrhythmia and cardiac insufficiency, liver damage, jaundice and so on.
Symptom
Symptoms of hemolytic uremic syndrome in children Common symptoms Weak diarrhea, loss of appetite, thrombocytopenia, abdominal pain, mucus, azotemia, arrhythmia, hemorrhagic tendency
Typical clinical manifestations often have prodromal symptoms, mainly gastrointestinal manifestations, abdominal pain, diarrhea and vomiting, may have fever, lethargy, fatigue, loss of appetite and other non-specific manifestations, severe abdominal pain with abdominal muscle tension, like anxious Abdominal disease; diarrhea can be watery stools, more common bloody stools and mucus, this period lasts for several days to one week, occasionally up to 2 months.
After the prodromal period, the acute phase occurs in the asymptomatic period for several days, hemolytic anemia, acute renal failure and thrombocytopenia, the child is obviously pale, the clinical jaundice is not significant or only the face is lemon yellow, and the initial hemolytic crisis When the elephant occurs, the hemoglobin drops by 30~50g/L within a few hours; the clinical manifestations of acute renal dysfunction are different, the lighter ones only have a decrease in urine output, and the renal function is mildly reduced, but most of the children have oliguric acute renal function. Depletion, oliguria can last for 2 weeks or even more than 2 weeks, with azotemia, metabolic acidosis, hyperkalemia and other acute renal failure, and can be due to anemia, high blood volume and electrolyte imbalance Causes congestive heart failure; thrombocytopenia causes bleeding, mainly gastrointestinal bleeding, visible skin ecchymosis, occasionally subdural or retinal hemorrhage.
Due to the extensive microvascular thrombosis of HUS, it can cause multiple system damage. Except for the gastrointestinal tract and kidney, especially the central nervous system is more common. It is the most common cause of death. The nervous system symptoms are irritating, lethargy, anxiety. Nervousness, hallucinations, disorientation, convulsions and coma, some of which have neurological sequelae, such as learning difficulties, abnormal behavior, severe mental retardation or epilepsy, cardiovascular system impairment of hypertension, arrhythmia and cardiac insufficiency; Patients with impaired pancreas may have temporary or permanent pancreatic endocrine insufficiency; may have transient liver damage, occasionally cholestatic jaundice; lung, muscle, skin and retinal damage are rare.
If there are:
1 oliguria is greater than 14 days;
2 no urine is greater than 7 days;
3 extrarenal organic damage, consider a serious case, HUS patients associated with Shigella infection, the condition is serious, there is no interval between gastroenteritis and this syndrome, and often have DIC, poor prognosis, mortality high.
1. The clinical features of D+HUS are most common in infants and young children. Argentina reported that the age of onset <90% accounted for 90%, and there was no significant difference in gender. It was more common in summer and had a small epidemic.
(1) prodromal period: D+HUS children with diarrhea, vomiting, abdominal pain, can have watery or bloody watery stools, the prodromal period is generally about 4 days, after 1 to 5 days (can also reach several weeks ) enters the acute phase during the asymptomatic period.
(2) acute phase: often vomiting, diarrhea, weakness, low fever onset, followed by pale, jaundice, subcutaneous ecchymosis, oliguria, a small number of convulsions, 60% of patients with oliguria lasting about 1 week, no urine, half The patient lasted for about 3 days, the critically ill patients entered the anorectal renal failure, more than half of the patients had hypertension, and 1/3 of the children had central nervous system involvement, including exercise, muscle tone changes, ataxia, convulsions, hemiplegia, etc. 3% to 5% of cerebral edema and coma, is also one of the most common causes of death in the acute phase, 40% of patients may be associated with liver, pancreatic damage, other such as heart, lung, muscle, skin and retina can be affected, but less common .
Siegler et al. accumulated 20 years of clinical experience in D+HUS, defined as severe cases: age <2 years old, no urine in the prodromal period, no urine lasting more than 7 days, oliguria greater than 14 days, white blood cell count higher than 20×109 / L and associated with extrarenal damage (extra-renal damage accounted for about 25%, mainly refers to damage to the nervous system such as convulsions, coma, etc.).
Caletti et al. performed an average of 11.2 years of follow-up in 30 children with D+HUS with persistent proteinuria, hypertension, and renal dysfunction, and underwent renal biopsy. The results indicated that 17 patients had focal segmental renal dysplasia. The ball was hardened with hyaline changes, 9 cases were diffuse mesangial proliferative nephritis, 2 cases were diffuse glomerular sclerosis, and 2 cases were mild lesions.
2. Secondary HUS The disease is rare in children, the most common infection is streptococcal pneumonia or sepsis, followed by -hemolytic streptococcus, mycoplasma infection, etc., no seasonal differences, the most common prodromal symptoms are upper respiratory tract infection, vomiting , fever, anemia, urinary tract infection, convulsions, etc.
In addition to the HUS triad, the clinical manifestations are characterized by high blood pressure, severe neurological damage, frequent ESRD, and high recurrence rate. The main difference between pathological changes and D+HUS is prominent small arterial disease, vascular endothelial cell proliferation and mesangial cell proliferation. Compared with D+HUS, renal biopsy of D-HUS recurrence cases showed that glomerular arteriolar endothelial cells and myometrial cells proliferated similarly to hypertension.
Examine
Examination of hemolytic uremic syndrome in children
1. Blood examination severe hemolytic anemia: repeated hemolysis can occur within a few days to several weeks, reticulocytes increase, medullary red blood cells increase, blood-stained protein decreases, blood routine shows hemoglobin and hematocrit decrease, platelet decline For several days to several weeks, peripheral blood smears can be seen in weird shape red blood cells, helmet-shaped cells and broken red blood cells. Biochemical tests show metabolic acidosis, hyperkalemia, hyperphosphatemia and hypocalcemia, low dilution. Blood sodium, azotemia, increased bilirubin and transaminase, decreased total protein and albumin, and hyperglycemia in patients with pancreas.
2. Urine examination: hematuria, proteinuria and hemoglobinuria, urinary sediment microscopic examination with red blood cell debris, white blood cells and casts.
3. Fecal examination: After typical diarrhea, HUS relies on fecal bacterial culture and serological typing. EHEC 0157:H7 is separated by immunomagnetic separation technique, which is convenient and rapid to culture.
4.Coombs test: mostly negative, erythrocyte enzyme activity is normal.
5. Other
(1) Prothrombin time: Partial thromboplastin time is normal or slightly shortened, V, VIII factor is normal or slightly increased, fibrin cleavage product is increased, and ATIII can be decreased.
(2) Serum C3, C4 and CH50 can be decreased, C3 can be deposited in the glomerulus of some patients, serum IgG concentration begins to decrease, and IgA and IgM increase, and IgM deposits are often detected in the glomerular mesangial area. Fibrinogen deposition is common.
(4) Some patients have an increase in BUN.
(5) Some patients may have increased serum cholesterol, triglycerides and phosphorus.
Other auxiliary examinations: routine X-ray, chest electrocardiogram, B-ultrasound, brain CT and other examinations.
1. Electrocardiogram, B-ultrasound and X-ray examination of patients with myocardial damage and central nervous system lesions, may have ECG, EEG, brain CT, brain MRI and other corresponding abnormal changes.
2. Renal pathological changes are generally divided into three types: vascular type, glomerular type, and renal cortical necrosis according to light microscopy. IgM, C3 and cellulose are deposited on the glomerular vessel wall by immunofluorescence. Electron microscopy showed capillary endothelial cell proliferation, swelling and shedding, red blood cell debris in the lumen, platelets and condensed cellulose, tubular atrophy and interstitial fibrosis and globular or segmental glomerulosclerosis, typical Pathological features are extensive glomerular thrombosis in the kidney, the renal histological changes of the disease are divided into 4 groups, namely focal segmental glomerulosclerosis, diffuse mesangial proliferative nephritis, diffuse renal small The ball is hardened and has a small lesion type.
Diagnosis
Diagnosis and diagnosis of hemolytic uremic syndrome in children
diagnosis
The child has a history of prodromal gastrointestinal symptoms, clinically seen acute hemolytic anemia, thrombocytopenia and acute renal function decline, manifested as pale, decreased urine output, urine test red blood cells, protein and cast, blood picture anemia, thrombocytopenia, smear see Heterotypic red blood cells and debris, blood biochemical changes in acute renal failure, can diagnose this disease, the diagnosis of this disease is:
1. Evidence of hemolytic anemia microvascular hemolytic anemia.
2. Thrombocytopenia.
3. Coagulation abnormalities thrombin time prolonged, FDP increased.
4. Progressive renal dysfunction BUN and Scr gradually increased, accompanied by proteinuria, hematuria, tubular urine.
5. There are pioneer infections This disease often has the basis of pioneer infection, more common in infants and young children, more common in pregnant women and postpartum in adults.
6. Pathological changes Characteristics Renal biopsy showed platelet aggregation and thrombosis in the capillary lumen, and edema and fibrinoid necrosis in the renal arterioles.
Differential diagnosis
The disease needs to be differentiated from TTP first. In addition, it needs to be associated with malignant hypertension, SLE, scleroderma, glomerulonephritis after acute streptococcal infection, acute nephritis, nephrotic syndrome with intravascular thrombosis, and The septicemia of Gram-negative bacteria with multiple organ failure should be differentiated from toxic or ischemic tubular necrosis in infancy, and older children should be differentiated from renal lesions caused by connective tissue disease.
