autoimmune hemolytic anemia in children
Introduction
Introduction to autoimmune hemolytic anemia in children Autoimmune haemolytic anemia (AIHA) is an acquired immune anemia that produces autoantibodies that react with red blood cell autoantigens and adsorbs on the surface of red blood cells, causing premature destruction of red blood cells. And a hemolytic anemia produced. Can occur at any age, the most common in childhood is the neonatal homologous anemia, followed by AIHA. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: jaundice, acute renal failure, hypersplenism
Cause
The cause of autoimmune hemolytic anemia in children
(1) Causes of the disease
The classification of AIHA is classified according to the cause, classified according to the type of antibody, and classified according to the onset of illness and clinical course.
1. According to the cause classification
Divided into two types of idiopathic AIHA and secondary AIHA, pediatric patients are mostly idiopathic, accounting for about 70%.
(1) Idiopathic: The cause is unknown.
(2) Secondary: Common causes are:
1 infection: can be caused by bacteria, viruses, mycoplasma or vaccination, pathogens including typhoid, streptococci, Staphylococcus aureus, tuberculosis, hepatitis virus, giant cell inclusion body virus, Epstein-Barr virus, herpes virus, influenza virus, adenovirus, Mumps virus, infectious mononucleosis, chickenpox, rubella and Mycoplasma pneumoniae (atypical pneumonia), spirochete infection (such as leptospirosis).
2 immune diseases: common in systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, idiopathic thrombocytopenic purpura, immunodeficiency disease, no gamma globulinemia, abnormal gamma globulinemia and bone marrow Transplantation, etc.
3 malignant tumors: such as leukemia, lymphoma, Hodgkin's disease and so on.
4 kinds of drugs: can be through hapten drug-dependent non-specific antibodies (such as penicillins, cephalosporins, etc.) or through immune complexes (such as quinine, quinidine, etc.) or induce true autoantibodies (such as methyl Dopa, levodopa, etc.) destroy red blood cells, hemolytic anemia, drug-induced AIHA mainly has three types:
A. Penicillin type: also known as drug adsorption type, the drug adsorbs on the surface of red blood cells to form a new antigen, the immune system manufactures antibodies, usually IgG is combined with it to cause hemolysis, and AIHA caused by penicillin, cephalosporin, tetracycline, etc. This type.
B. methyldopa type: AIHA caused by -methyldopa is autoimmune, 60% found in HIA_B7.
C. Immune complex type: This is because IgM reacts with the drug, activates the complement system, and C3b deposits on the surface of red blood cells, which causes macrophages to attack and phagocytose the C3b-bearing red blood cells. A few IgG antibodies can also be condensed. Similar to IgM, seen in paroxysmal cold hemoglobinuria, this antibody binds to the blood group P antigen on the erythrocyte membrane and hemolytic anemia occurs by activating complement.
2. Classification according to the nature of the antibody
It is divided into two types: warm antibody type and cold antibody type. The warm antibody type has the strongest effect at 37 °C, and is divided into warm incomplete antibody and warm hemolysin. The temperature incomplete antibody is an incomplete antibody. IgG type; warm hemolysin is IgM type, cold antibody type is the strongest at 4 ° C, is a complete antibody, it can be divided into cold agglutinin and cold hemolysin, the former is IgM type, can cause condensation set Syndrome; the latter is IgG type, can cause paroxysmal cold hemoglobinuria, both types have mixed type.
3. According to the onset of illness and clinical classification
It is divided into acute, subacute and chronic types. Acute and subacute types are more common in infants and young children. Chronic types are more common in children and adolescents.
(two) pathogenesis
1. The mechanism of red blood cell autoantibody production
The mechanism of production of anti-erythrocyte autoantibodies is not fully understood, and there are mainly the following viewpoints:
(1) Erythrocyte antigenicity changes: normal organisms do not produce antibodies to their own red blood cells. After viral infection or certain chemical substances bind to the erythrocyte membrane, the antigenicity of red blood cells is changed to produce autoantibodies.
(2) Abnormal immune system: due to the influence of certain factors (such as immunodeficiency, malignant tumor, thymic disease, genetic mutation, etc.), it causes the immune surveillance function of the body to disorder, and the immune active cells in the body lose their ability to recognize their own red blood cells. Thereby producing autoantibodies, due to inhibitory T cell reduction and dysfunction, causing inhibitory (or inhibition-induced) T cell imbalance, the corresponding B cell response is too strong, resulting in autoimmunity, in addition, due to B cell internal abnormalities or T Cells that produce excessive lymphocytes that stimulate B cells (such as interleukin-6) cause antigen-independent polyclonal activation of autoreactive B cells, which may also be related to autoimmune responses.
2. Hemolysis mechanism
(1) Immune clearance of red blood cells: In vivo, self-erythrocytes are first conditioned by autoantibodies, and then the conditioned red blood cells are directly destroyed in the blood circulation (intravascular hemolysis) and/or cleared by macrophages in tissues (extravascular hemolysis) ), the conditioned red blood cells are mainly located in the spleen, and a small number of macrophages located in the liver recognize and scavenge, and macrophages are coated with specific IgG (especially IgG1 and IgG3) Fc segment receptors and C3b receptors. There are IgG and/or C3 red blood cell interactions, at least two IgG molecules binding to the surface of red blood cells to trigger the deposition of C3b in the erythrocyte membrane. The IgG subclass not only binds to the erythrocyte in the macrophage Fc receptor. It plays an important role (IgG3>IgG1) and is also required for complement activation. The IgG subclass activates complement in order of strength: IgG1>IgG3>IgG2>IgG4, and the simultaneous presence of IgG and C3b on the erythrocyte membrane accelerates red blood cells. Immune clearance, the amount of IgG bound to red blood cells can also affect the rate of hemolysis, in some cases, the number of IgG molecules per red blood cell is less than 200 is still enough to cause hemolysis, in addition, the spleen The environment also has a special role in immune clearance. In the slow blood circulation in the spleen, the relatively low plasma IgG concentration in the spleen sinus can weaken the competitive binding of plasma IgG and IgG-coated red blood cells to the Fc receptor, thus facilitating the giant The phagocytes interact with the conditioned red blood cells and effectively capture them.
(2) Damage of red blood cells: Macrophages can not only directly digest the conditioned red blood cells, but also the enzymes with proteolytic activity on the surface can also digest part of the erythrocyte membrane, thereby producing spherical cells, which slowly pass through the spleen microcirculation. It is easy to rupture, which is the main mechanism of extravascular hemolysis of IgG-coated red blood cells (with or without C3b). In addition, C3b can be degraded to C3d due to the regulatory proteins of the complement system (C3b inactivating factor and 1H globulin). Thus, the process of complement activation on the surface of the conditioned red blood cells is blocked, the red blood cell antibody is spontaneously released, and the red blood cells coated with C3d survive, so intravascular hemolysis is relatively rare.
(3) Complement participates in erythrocyte lysis: autoantibody and complement after binding to erythrocyte antigen, through the traditional complement activation pathway C1a, the activated complement (C3b, C5b, etc.) is inserted into the erythrocyte membrane, so that the erythrocyte membrane is produced inside and outside. The water-soluble channels of the same cause the countercurrent of the electrolyte and the infiltration of water, causing the red blood cells to swell and dissolve.
(4) Weak agglutination of red blood cells: Red blood cells combined with autoantibodies and complements, due to the reduced mutual negative charge of the surface, causing weak agglutination between red blood cells, and the agglutinated red blood cells collide with each other in the blood circulation, causing red blood cells to deform and rupture. The red blood cells that become spherical are more easily destroyed in the spleen, causing hemolysis. In summary, the macrophage-mediated hemolysis mechanism is an important mechanism leading to erythrocyte injury of AIHA, but the action of cytotoxic lymphocytes (NK cells) It cannot be ruled out that the function of reticuloendothelial cells is also related to the degree of immune clearance of red blood cells, which may explain why the infection of the virus or bacteria causes the disease to worsen. The hemolysis caused by the warm antibody type is mainly extravascular hemolysis, when there is complement involvement. Intravascular hemolysis can also occur, cold antibody-type immune hemolytic anemia can be divided into cold hemagglutinin syndrome (cold hemagglutinin syndrome) or condensed disease and paroxysmal cold hemoglobinuria; the former by the child's own cold agglutinin IgM caused.
A small number can be caused by IgG or IgA, the latter is IgG type cold antibody, these antibodies coagulate with their own red blood cells in the cold and complement, mainly in the liver to destroy or cause intravascular hemolysis, cold antibody type is often secondary to various Infection may be caused by a similarity between various pathogenic microorganisms and human erythrocyte surface antigens. It is also known as cross antigenicity. It is also believed that pathogenic microbial metabolites bind to proteins in the erythrocyte membrane in vivo, denatured proteins and become a new type of infection. The antigen, thus stimulating the body's immune system to produce autoantibodies, cold agglutinin disease: IgM cold agglutination can form agglutination with autologous red blood cells under the appropriate low temperature conditions and complement, causing intravascular hemolysis, heat amplitude of cold agglutinin (the minimum temperature required for agglutination of red blood cells) is related to the titer of lectin. The heat amplitude of the condensation agglutinin is different in each case, and the clinical manifestations are also different. The cold hemolysin is hemolyzed. At low temperature (below 16 ° C), this antibody Binding to the P-type antigen on the erythrocyte membrane, the traditional pathway of complement is activated during rewarming, and the resulting C3b attachment On the erythrocyte membrane, the multi-C9 membrane attack complex directly causes erythrocyte membrane damage, ion leakage, especially potassium ion loss, sodium ions enter the red blood cells, and finally red blood cells swell and hemolysis, AIHA can also be complicated with immune system proliferative diseases For example, lymphocytic leukemia, malignant lymphoma, etc., in addition, AIHA often occurs in collagen vascular diseases.
Prevention
Pediatric autoimmune hemolytic anemia prevention
Mainly to prevent secondary AIHA and condensed disease, such as doing a good job in vaccination, health, physical fitness, balanced diet, active prevention and treatment of various infectious diseases, no abuse of antibiotics, reducing environmental pollution, avoiding exposure to toxic substances, etc. Wait.
Complication
Pediatric autoimmune hemolytic anemia complications Complications, jaundice, acute renal failure, hypersplenism
Often acute infection, progressive anemia, jaundice, splenomegaly; hemoglobinuria often occurs, severe acute renal failure; can be complicated by hypersplenism; a few with thrombocytopenia, skin, mucosal bleeding, can be caused by bleeding death. The cold antibody type can be complicated by Reynolds signs and the like.
Symptom
Symptoms of autoimmune hemolytic anemia in children Common symptoms Fatigue repeated infection of jaundice thrombocytopenia hemolytic anemia bleeding tendency proteinuria abdominal pain hepatosplenomegaly
The clinical manifestations of this disease vary with the etiology and type of antibody. Pediatric patients are more common in acute type and more often than adult patients.
Warm antibody type
(1) acute type: 70% to 80%, most of the patients are infants and young children, occasionally in newborns, the peak age of onset is about 3 years old, male majority, often 1 to 2 weeks before the onset of acute infection history, from Sudden illness, accompanied by fever, chills, progressive anemia, jaundice, splenomegaly, hemoglobinuria often occurs, a small number of patients with thrombocytopenia, skin, mucosal bleeding, clinical progression is self-limiting, after 1 to 2 weeks of onset Hemolysis can stop by itself, 50% of patients recover completely within 3 months, the longest is no more than 6 months, severe hemolysis, acute renal insufficiency, oliguria, no urine and azotemia, acute type The treatment of adrenocortical hormone is better, the prognosis is generally good, and most of them can be completely recovered, but those with thrombocytopenia may die due to bleeding.
(2) Subacute type: Most patients are children under 9 years old, with secondary sexual majority. The flu or vaccine injection history is often 1 to 2 weeks before onset, and the onset is slow. The main symptoms are fatigue and anemia, jaundice. And hepatosplenomegaly, generally no systemic disease exists, a small number of patients have a tendency to hemorrhage due to combined thrombocytopenia, often recurrent in the course of the disease, making the symptoms worse, the course of the disease is generally about 2 years, some patients get cured after treatment, there are The condition is prolonged and converted to chronic type. Patients with thrombocytopenia may die from bleeding. The cause of penicillin is related to the dose of penicillin. If the daily dose exceeds 1.2 million U, hemolysis is rare, even if hemolysis occurs. Light, hemolysis quickly subsided after stopping the drug.
(3) Chronic type: The majority of patients are school-age children, with the majority of primary, occasionally secondary to connective tissue diseases such as systemic lupus erythematosus, slow onset, progressive or intermittent hemolysis, repeated infection Hemolysis can be aggravated, the main symptoms are anemia, jaundice, hepatosplenomegaly, often accompanied by hemoglobinuria. These symptoms often recur, hemolysis can last for months or years, and the course of primary disease can be as long as 10 to 20 years. The prognosis of secondary patients depends on the primary disease. Co-infection can aggravate the condition. The prognosis of thrombocytopenia is mostly serious, and even the hemolytic crisis may occur. Other blood cell components are often complicated, such as neutrophils or thrombocytopenia ( Even syndrome), the efficacy of adrenal glucocorticoids is not certain, the mortality rate is about 10%, mainly in cases with systemic diseases.
2. Cold antibody type
(1) cold agglutinin disease: acute patients are mostly children under 5 years old, often secondary to mycoplasmal pneumonia, infectious mononucleosis, cytomegalovirus infection, etc., leptospirosis and chickenpox can also occur, onset Suddenly, the main manifestations are acral cyanosis and Raynaud's sign, with anemia and jaundice of varying degrees. The clinical process is self-limiting. When the primary disease is cured, the disease is cured. Chronic patients are mainly seen in the 50-year-old or older. The elderly, mostly primary, can also be secondary to lupus erythematosus and chronic lymphadenitis, the condition is slow, often recurrent, and the prognosis is serious.
(2) paroxysmal cold hemoglobinuria (PCH): not uncommon in China, after 1 year old children can be ill, more secondary to congenital syphilis, measles, mumps, chickenpox and other diseases, a small number For the primary, the sick child suffers from cold, most of the onset of sudden onset, sudden acute intravascular hemolysis, manifested as fever, chills, abdominal pain, low back pain, anemia and hemoglobinuria, occasionally with Raynaud's sign, mostly lasting for several hours That is to relieve, after remission; if it is cold again, it can relapse.
Examine
Examination of autoimmune hemolytic anemia in children
Warm antibody type
(1) Peripheral blood: acute patients often have heavier anemia. Most patients with chronic and subacute patients have mild anemia. Most cases have hemoglobin <60g/L, spherical and polychromatic red blood cells are more common, acute type Reticulocytes are often >10%, and chronic types are sometimes reduced. The main reason is that IgG antibodies can bind to young red blood cells and reticulocytes, reducing red blood cells and reticulocytes in the bone marrow, and mildly increasing subacute types. In the case of aplastic anemia, reticulocytes can be extremely reduced, the total number of white blood cells is usually increased, and leukemia-like reactions can occur. In the absence of Even syndrome, platelets are usually normal.
(2) Erythrocyte osmotic fragility test: The fragility is increased when the disease progresses, and the symptoms can be normal when the symptoms are relieved.
(3) Determination of bilirubin and globin: serum indirect bilirubin increased, urobilinogen increased, and haptoglobin decreased or disappeared.
(4) Coombs' test: The positive result of this test is an important basis for the diagnosis of this disease. The test is divided into direct antiglobulin test (DAT) and indirect antiglobulin test (IAT). The former is to measure the incomplete antibodies adsorbed on the surface of red blood cells, the latter is to measure the incomplete antibodies in the serum. Most of the two tests are positive, but very few patients (2% to 4%) are always negative. The occurrence of this condition is mainly related to the lack of sensitivity of the anti-human globulin test. When the IgG molecules attached to the surface of each red blood cell are 40-200, hemolysis can be caused, but due to insufficient IgG molecules, the direct test can be performed. Negative reaction, only when the IgG molecules on the surface of each red blood cell reach 200-500 or more, the positive result can be detected. In order to improve the sensitivity of the test, people have applied radioimmunoassay or complement-binding antibody consumption test to determine the red blood cell surface. An IgG molecule to confirm the diagnosis of the disease. In addition, the negative of this test is also related to the limitations of the anti-human globulin reagent used, because Only without IgA autoantibodies IgG and IgM antibodies, these rare cases, the available anti-human globulin serum IgA specific for direct detection of 0.5% to 2.5% of patients.
(5) Enzyme-treated erythrocyte agglutination test: O-type red blood cells of the Rh genotype treated with trypsin, papain or bromelain were respectively incubated with the patient's serum, and the agglutination reaction indicates that there is anti-erythrocyte free antibody in the serum of the patient, and the temperature is high. Autolysin (IgM) allows the enzyme-treated red blood cells to dissolve directly.
(6) Bone marrow: The bone marrow red system is obviously hyperplasia.
2. Condensed disease
(1) Blood: mild to moderate anemia, blood smear: red blood cell morphology can be normal.
(2) Cold agglutinin test: The blood of this patient contains cold agglutinin (mostly IgM, only very few IgA or IgG), and the cold agglutinin and its red blood cells agglutinate with the participation of cold and complement. The positive test is an important basis for the diagnosis of this disease. The titer of this test is increased at 4 °C, the titer can be as high as 1:1000 or more, and the titer of a few patients at 2 to 5 °C is 1: (16 ~ 256), the temperature Aggregation disappears when approaching body temperature.
(3) Direct anti-human globulin test: positive.
3. Paroxysmal cold hemoglobinuria
(1) Blood picture: Hematological examination results with typical intravascular hemolysis.
(2) Urine: Repeatedly the author appeared hemosiderin urine.
(3) Positive cold and cold hemolysis test: The serum of the patient has its own cold hemolysin (non-lectin IgG), which is a self-cold antibody against red blood cells. When the patient is at or below 16 °C, cold antibodies and The combination of its own red blood cells; then add serum or guinea pig serum (providing complement) matching the patient's red blood cell blood type, when the temperature rises to 37 ° C, hemolysis occurs, the positive test is an important basis for the diagnosis of this disease.
(4) Direct anti-human globulin test: When hemoglobinuria is onset, it is often positive, and the interval between hemolysis is negative. Routine X-ray films, B-ultrasound and electrocardiogram are routinely performed, and others are selected according to clinical needs.
Diagnosis
Diagnosis and diagnosis of autoimmune hemolytic anemia in children
diagnosis
According to the clinical manifestations of hemolysis, the anti-human globulin test is positive, and the diagnosis can be made. After the diagnosis is established, it should be further determined to be primary or secondary. For this, it can be considered in combination with clinical manifestations. In patients with AIHA, the primary disease usually occurs after hemolytic anemia. Therefore, long-term follow-up observation can detect the primary disease in time. In addition, serological findings may also contribute to primary and secondary AIHA. In general, IgG is more common in patients with chronic primary disease, while IgM and complement are more common in secondary patients. For suspicious cases with negative anti-human globulin test, the diagnosis depends mainly on clinical manifestations and adrenal gland. Glucocorticoid treatment response to determine, such as the use of adrenal glucocorticoids, combined with clinical considerations of the disease, cold agglutinin disease and PCH diagnosis, in addition to clinical manifestations and anti-human globulin test, the former condensation The lignin test was positive, and the latter was positive for cold and hot hemolysis test, all of which have a diagnostic significance.
Differential diagnosis
In the differential diagnosis, the disease should be differentiated from other hemolytic anemia such as globin-forming anemia, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, infectious mononucleosis combined with hemolysis, and cold antibody type needs Paroxysmal nocturnal hemoglobinuria was identified, the latter was positive for Ham and Rous tests, and negative for anti-human globulin test.
