Pediatric primary immunodeficiency disease

Introduction to primary immunodeficiency disease in children The immunodeficiency disease caused by congenital genetic factors, such as congenital mutations, deletions, etc., is called primary immunodeficiency disease (PID). basic knowledge The proportion of sickness: 0.01% Susceptible people: children Mode of infection: non-infectious Complications: meningitis osteomyelitis pneumonia bronchiectasis

The cause of primary immunodeficiency in children

(1) Causes of the disease

Immunodeficiency diseases can be caused by a certain protein defect produced by a certain cell line, or can be caused by multiple system defects. The following are common causes of immunodeficiency diseases.

1. Genetic defects: single gene defects expressed in multiple tissues (such as ataxia telangiectasia, adenosine deaminase (ADA) deficiency, etc.), limited to single-gene defects in the immune system (such as sexual association Gammaglobulinemia with tyrosine kinase deficiency, abnormality of T cell antigen receptor with chain, etc., familial susceptibility to multifactorial diseases (such as common variant immunodeficiency disease).

2. Drugs and poisons: immunosuppressants (such as corticosteroids, cyclosporine, etc.), anticonvulsants (such as lenidine).

3. Nutritional or metabolic diseases malnutrition, protein-losing enteropathy (such as intestinal lymphatic dilatation), vitamin deficiency (such as vitamin B12 deficiency), trace element deficiency (such as intestinal dermatitis with zinc deficiency) .

4. Infection: temporary immunodeficiency (such as chickenpox, rubella, etc.), permanent immunodeficiency (such as HIV infection, congenital rubella infection)

5. Chromosomal abnormalities: DiGeorge abnormalities (such as 22q11 deletion), selective IgA deficiency (such as 18-tris).

It can be seen from the above that the etiology of immunodeficiency diseases is complicated. In clinical manifestations and laboratory tests, primary and secondary immunodeficiency diseases are often not easily distinguished. In clinical practice, primary immunodeficiencies are often accompanied. Secondary immunodeficiency in other systems, such as patients with non-gammaglobulinemia, may present secondary T cells or monocyte subpopulations that inhibit antibody production from normal B cells. In addition, the same clinical manifestations and laboratory abnormalities It can be caused by different gene defects or pathogenic factors, and different point mutations of the same gene can cause inconsistency in the severity of the disease. Due to the influence of these factors, it is sometimes difficult to make a clear diagnosis of the cause of immunodeficiency disease.

In order to facilitate the search for the cause of immunodeficiency diseases, immunodeficiency diseases are classified according to whether they involve T cells, B cells, macrophages or complement. This classification has clinical utility, but it also has its Insufficient, many immunodeficiency diseases can not be clearly classified into a certain category, and the naming of this classification sometimes causes confusion of understanding, such as the high-IgM syndrome with antibody defects, but the defective gene (The gene encodes a ligand for CD40) is expressible on activated T cells.

At present, the analysis of immunodeficiency diseases from the perspective of cell biology (such as DNA replication, information transmission and cell adhesion) has received more and more attention, which not only deepens the understanding of the process of normal cell differentiation, but also can be immune to certain immunity. Defective disease has a clear genetic diagnosis. As more and more immunodeficiency diseases can obtain a clear genetic diagnosis, the genetic diagnosis of immunodeficiency disease will become more important, because accurate genetic diagnosis can be used for genetic diagnosis. Providing helpful information and helping to develop a treatment plan.

(two) pathogenesis

In 1971, the WHO Expert Committee of Experts established the principle of PID naming: named after the pathogenesis of the syndrome, pathophysiological changes, especially genetic characteristics, and abolished the traditional names of people and places, such as changing the Bruton disease to X-linked. Gammaglobulinemia (XLA), the Swiss type of agammaglobulinemia was changed to severe combined immunodeficiency disease (SCID), etc. In 1971, the WHO Expert Committee conducted the first global unified classification according to the new nomenclature. The understanding of various PIDs has gradually deepened, and the classifications have been re-examined every 2 to 3 years. The PIDs listed below are the names of disease classifications used in the 7th revision of 1997.

1. Combined immunodeficiency: Both T and B cells may have obvious defects in this group of diseases. The clinical manifestations are severe fatal infections in infants, cellular and antibody responses are defective, and peripheral blood lymphocytes are reduced. T lymphocyte-based

(1) severe combined immunodeficiency (SCID):

1T cell defect, B cell normal SCID (TS SCID):

AX-linked TB SCID: The disease is caused by mutation of the interleukin-2 receptor r chain (IL-2Rr) gene located on Xq13.1, which is a common disease in SCID. Recently, IL-2Rr was also found to be IL. -4, IL-7, IL-9 and IL-15 receptor common r-chain (re), also known as IL-2Rrc, clinical manifestations of early repetitive, severe fungal, bacterial and viral infections and graft versus host Response (GVHR), peripheral blood T cells are lacking or significantly reduced, B cells can be normal or increased, but serum IgM, IgA, IgG levels are low, lymphocyte proliferation activity is low, and more than 1 year old died of serious infection, the severity of the disease depends on In the location and nature of gene mutations, the success rate of bone marrow transplantation in this disease can reach 90%, and the transgenic rc gene therapy is still in the experimental stage.

B. Autosomal TB SCID: Due to mutation of the intracellular kinase Jak3 gene, immunological changes and clinical manifestations are the same as TB SCID.

Both 2T and B cells lack SCID (TB-SCID):

A. RAG-1/RAG-2 deficiency: RAC-1/RAG-2 deficiency causes TB-SCID to be caused by recombinant activation gene-1 (RAG-1) or RAG-2 mutation, which occurs in infancy, peripheral blood T Both the B cell count and the B cell count were significantly reduced, but the NK activity was normal or elevated. The disease was caused by the RPG1/RAG2 mutation in the 11p13-encoding VDJ gene recombinase, which enabled T cell receptor (TCR) and B cell surface immunoglobulin (SIg). The VDJ structural reorganization is impaired, and the peripheral blood T and B cells of the patient are all reduced. The child has a serious recurrent infection 2 to 3 months after birth.

B. Adenosine deaminase (ADA) deficiency: ADA gene mutation, ADA deficiency can lead to adenosine, deoxyadenosine, deoxyadenosine triphosphate (dATP) and S-adenosyl homo-halophilic acid in cells (S-adenosylhomocysteine) accumulation, they have a cytotoxic effect, inhibit T and B cell proliferation and differentiation, most cases occur in early years, if the genetic mutation site affects ADA function less, it can occur in older children and adults, symptoms also light.

All TB-SCIDs are autosomal recessive.

(2) Immunoglobulin deficiency with high IgM (high IgM syndrome, HM): 70% is X-linked inheritance, and the rest is autosomal recessive inheritance; characterized by intracellular B cell Ig transition disorder, The result is that IgM is normal or elevated, while IgG, IgA and IgE are both reduced or absent. X-linked high IgM is not able to bind to CD40 on the surface of B cells due to mutation of CD40 ligand on the surface of T cells. Activation stimulation is the cause of Ig conversion disorder. The laboratory found that T and B cell counts are normal, T cell proliferation response is normal, but T cell-dependent B cell proliferation response is low. In vitro lymphocyte culture, T cell expression of CD40L is reduced. One of the main points, but pay attention to the common variant immunodeficiency disease (CVID) and other diseases, such as reduced CD40L expression, CD40L gene mutation analysis can be diagnosed, (3) purine nucleoside phosphorylase (PNP) defects: PNP lacks the accumulation of the toxic intermediate metabolite, guanosine triphosphate, which is particularly damaging to lymphocytes, especially T cells.

2. Immunodeficiency disease based on antibody deficiency: antibody defects may be due to developmental disorders of B cells themselves, or may be due to the failure of normal B cells to receive the synergistic signal stimulation of defective T helper cells, thus the antibodies in the past classification The defect disease is changed to an immunodeficiency disease mainly based on antibody defects, and its main clinical manifestation is repeated suppurative infection.

(1) X-linked agammaglobulinemia (XLA): This disease is also known as Bruton's disease, due to the deletion or mutation of the Bruton tyrosine kinase (Btk) gene located on Xq12.3~22. B cell development is blocked by the original B cells, very few mature B cells (CD20, CD19, SIg B cells less than 2%), showing minimal or absent peripheral blood B cells (1000 cells per count, B cells) The number is less than 5), the plasma cells are also lacking, the lymphoid germinal center is absent, and the blood IgM, IgG and IgA are significantly decreased or absent (IgG<2g/L, IgA<0.1g/L), the number of T cells and Normal function, due to different mutation sites, Btk protein expression function is also different, clinical manifestations vary in severity, so all boys with low Igemia should be screened for Btk gene, most children from June to December after birth Repeated suppurative infection occurs mainly in the respiratory tract, and there are also systemic infections. Btk gene analysis can confirm the disease. One third of the children can not find a positive family history. Lifetime IVIG is effective in treating this disease. Bone marrow stem cell transplantation may be effective. Gene therapy is under investigation.

(2) Selective IgG subclass defects: IgG subclass defects can be considered when the concentration of 1-2 IgG subclasses is lower than that of children of the same age. Since IgG1 accounts for 70% of total IgG, IgG1 defects are always accompanied. There is a decrease in total IgG. In the Caucasian population, low levels of IgG3 are common in adult cases, while in children, IgG2 is often low. In our country, IgG subclass defects are mainly IgG3, IgG4 accounts for less than 5% of total IgG, and normal children sometimes It is difficult to measure, so it is not appropriate to diagnose IgG4 deficiency. When IgG2 and IgG4 are combined with defects, antibodies against polysaccharide antigens such as influenza bacillus, meningococcal and pneumococcal antibodies cannot be produced.

(3) common variable immunodeficiency syndrome (CVID): a group of unknown etiology, characterized by Ig low syndrome, multi-gene genetic theory to be confirmed, some patients with IgA deficiency can be converted to CVID, suggesting two diseases Can be energy-deficient at the same locus defect, contrary to XLA peripheral lymphoid atrophy, peripheral lymph node enlargement and splenomegaly in children with CVID, autoimmune disease, lymphatic tumor and gastrointestinal malignant tumor, CVID Often in the elderly or adults, both men and women can be ill, these are different from XLA, repeated respiratory infections, including sinusitis, pneumonia and bronchiectasis, can develop chronic obstructive pulmonary disease, also susceptible to pyloric screw Bacterial, P. cerevisiae and other gastrointestinal infections and enteroviral meningitis, B cell Ig gene expression and Ig synthesis and secretion are not abnormal, but the number of B cells may be reduced, serum IgG, A of the sick children is significantly lower than normal peers, Secretory IgA levels are also low, SIgM, SIgG, and SIgA cells are normal, but cannot be converted to corresponding plasma cells. T cell abnormalities may be the key to disease. The expression of CD40L in patients with T cells decreased, and the activity of cytokines IL-4 and IL-6 secreted by T cells decreased or increased. It is reported that IL-2, IL-5 and IFN activities are decreased, and T cell dysfunction may be associated with cells. Related to information transmission disorders, such as the decline of phosphokinase C (PKC) activity, CVID genetic indefinite, can be autosomal recessive or dominant, but also X-linked, but more common is a sporadic case of no genetic family, The severity of the lesion is generally lower than XLA, and the diagnosis relies on the exclusion of other primary immunodeficiency diseases. IVIG replacement therapy can reduce the severity of the infection.

(4) IgA deficiency: IgA deficiency disease is a relatively common PID, but the incidence rate of the population is different. The incidence rate of white people is 1/500 to 1/1500, that of Japanese is 1/18500, and that of Chinese is about 1/5000~1. /10000, the pathogenesis of this disease is unknown, may be related to the imbalance of IgA regulation by B cells in TH2 cells. No IgA gene deletion or mutation is found at present. Some cases are autosomal recessive or dominant inheritance, and mild children may have no Symptoms or repeated respiratory infections in the infancy and intestinal, urinary tract infections, both men and women can be ill, there are several people in the family, most people can live to adulthood and old age, in some cases serum IgA can gradually rise to normal levels, Accompanied by autoimmune diseases, asthma and intestinal malabsorption, serum IgA is less than 0.05g / L, IgM, IgG is normal or elevated, secretory IgA is also significantly reduced, should avoid the use of gamma globulin, because it contains trace amounts of IgA, It can induce the development of anti-IgA antibodies (genuine class IgG2), but fortunately, a considerable number of children with IgA deficiency are accompanied by IgG2 subtype defects, and these people generally do not have an allergic reaction.

(5) Temporary hypogammaglobulinemia in infants: In normal infants, IgG from the mother's body has disappeared from March to April, serum IgG is at the lowest level, and IgG is gradually increased. Baby transient low-gambling bulbs Children with transient hypogammaglobulinemia of infant can not produce IgG in time, so serum IgG levels continue to decline, and gradually rise after about 3 years old. The mechanism is still unclear.

3. Immunodeficiency diseases with T cell defects: Most of the diseases in this group are newly discovered, and diseases that are still unclear in molecular genetics and etiology:

(1) CD4 T cell defects: peripheral blood CD4 T cell count decreased, cellular immune function is low, and serum Ig levels are normal or high, susceptible to cryptococcal meningitis, Candida and other opportunistic infections.

(2) CD7 T cell deficiency: peripheral blood CD7 T cell deficiency.

(3) IL-2 deficiency: IL-2 mRNA transcriptional expression disorder.

(4) Multiple cytokine deficiency: IL-2, IL-4 and IL-5 deficiency, lack of nuclear factor (NFAT) that activates T cells.

(5) Information transmission disorder: T cell calcium influx and diacylglycerol (DAG) expression are disordered after antigen stimulation, and the clinical manifestations are similar to SCID or CVID.

(6) Calcium influx disorder: T cell calcium influx mechanism is dysregulated, showing SCID.

4. Immune Defects Combined with Other Important Features In addition to immunodeficiency, these diseases have outstanding clinical manifestations:

(1) Eczema-thrombocytopenia with immunodeficiency (WAS): The WAS protein (WASP)-encoding gene is located at Xq11.22, and WASP is present in the cytoplasm of hematopoietic stem cells and cells differentiated therefrom. It is not clear that it may be related to intracellular information transmission and cytoskeletal reorganization. WASP gene mutation or deletion causes lymphocyte and platelet dysfunction. Early manifestations are bleeding tendency after birth, skin defect, bloody stool, and cranial Internal bleeding; eczema can be light and heavy, can be limited to the face; hepatosplenomegaly and repeated or chronic infection is another feature, the incidence of lymphoma and autoimmune vasculitis is high, the laboratory found that IgM decreased, IgA, IgE rose IgG is normal; antibody response is poor, anti-family lectin has low titer, lymphocyte proliferative response and phagocytic chemotaxis are reduced, platelet count is reduced, and volume is reduced. Most patients are in the age of 3 years before the bone marrow transplantation. Death due to severe bleeding or infection.

(2) ataxia telangiectasia (AT): characterized by progressive cerebellar ataxia and telangiectasia, the latter often occurs in the earlobe and ball-bound membrane, serum alpha-fetoprotein increased in 95 In the case of %, the early immunodeficiency was not obvious, and about 70% of the cases had abnormal immune function. The serum IgG2, IgG4, IgA and IgE decreased or decreased, and the antibody response decreased. The number and function of T cells are mostly weakened, and repeated respiratory infections gradually appear. Lymphocytes are very sensitive to radiation, and DNA damage is not easy to repair. Patients are prone to tumors and often cause death. The disease is autosomal recessive.

(3) DiGeorges syndrome: a part of a series of genetic abnormalities, 80% to 90% of cases with chromosome 22q11-ter deletion, this continuous gene deletion causes cardiac abnormality (cardiac abnormalitis) Abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia, so called "CATCH22", the number of T cells, especially CD8 T cells, is absent in the thymus Reduced, sick children are prone to viral infections. Due to hypofunction of the parathyroid gland, the child will develop hypocalcemia after birth; when the I~II pharyngeal arch is involved, a special face appears: wide eye distance, flat nose, small mouth and low ear; III-IV pharyngeal arch development Poor causes congenital heart disease, such as large blood vessel translocation, tetralogy of Fallot, although the thymus volume becomes smaller or atrophy and the outer embryonic tissue is replaced, but the immunodeficiency of this disease is light, and T cells appear in only about 20% of cases. Abnormal function, most children with age, T cell defects can be restored to normal by themselves, congenital malformation can be treated surgically, early infection can be given anti-infective and symptomatic treatment, bone marrow and thymocyte transplantation has been successfully reported.

5. Number of phagocytic cells and functional defects

(1) Severe congenital neutropenia (SCN, Kostmann syndrome): Peripheral blood neutrophil colony-stimulating factor (G-CSF) receptor gene translocation, but not G-CSF receptor protein In some cases, granulocytic aplasia or granulocytic acute leukemia occurs.

(2) chronic granulomatous disease (CGD): phagocytic cell bactericidal function is weakened, leading to chronic suppurative infection, granuloma formation, especially in lymph nodes, liver, lung and gastrointestinal tract, pathogen is staphylococci, large intestine 2,3 cases of H. oxysporum, Serratia, Nocardia and fungi (especially Aspergillus), the disease occurs in the first year of life, especially in the lungs, Staphylococcus aureus infection, phagocytic cell bactericidal function is low, the disease is formed Unique manifestations; a large number of lymphocytes, granuloma of tissue cell aggregation, located in various parts, the corresponding clinical manifestations, CGD can be divided into X-linked and autosomal recessive inheritance, X-linked CGD clinical performance is the heaviest, and Autosomal recessive CGD has mild symptoms, and the 91KD chain (gp91phox) gene in cytochrome b558, a component of X-linked CGD-derived reduced coenzyme II (NADPH) oxidase, causes superoxide, monomorphic oxygen. And H2O2, some cases are caused by Xp21 deletion, autosomal recessive CGD can be cytochrome 16 gene p22phox deficiency, or NADPH oxidase p67phox or p47phox defect, tetrazolium blue dye test (NBT) can be used as a preliminary screening for the diagnosis of this disease. Further diagnosis depends on NADPH oxidase activity determination and genetic analysis. About 50% of CGD patients die of infection before the age of 30. The principle of treatment is prevention and treatment of infections (such as sulfonamide synergists). And other sensitive antibiotics, keep indoors dry to avoid fungal infection, recombinant interferon can increase phagocytic oxidase activity (0.05mg/m2, 3 times a week, subcutaneous), corticosteroids are available for granulomatosis Treatment of 0.5 ~ 1mg / (kg · d) for several weeks, bone marrow transplantation and gene therapy have been successful cases.

6. Complement Defects: The generalized complement system involves a group of plasma proteins consisting of two parts:

(1) complement active components C1 to C9, factor B and mannose-binding lectin (MBL).

(2) complement regulatory protein, C1 inhibitor, C4 binding protein, factor D, factor I, properdin, factor H, decay accelerating factor (DAF, CD55) and protective factor (protectin, CD59).

Different complement component defects have different clinical manifestations. The common features are repeated infections and rheumatic diseases. The upstream components of complement such as C1, C4, C2, C3 are defective, and it is prone to repeated purulent infections, especially those with capsular polysaccharide antigen. Infection; downstream components C5 ~ C9 (also containing C3) defects are prone to Gram-negative bacterial infection, especially Neisseria infection, 1% to 15% of patients with sporadic meningococcal infection.

The mechanism of complement deficiency with rheumatic diseases is unknown, especially the upstream components C2, C4, C3 defects, the probability of rheumatic diseases is as high as 80%, much higher than the incidence of downstream component defects (C5 ~ C9) (10%), these main It is systemic lupus erythematosus, dermatomyositis, scleroderma, allergic purpura, vasculitis and membrane proliferative nephritis.

Androgen drugs, such as stanozolol or danazol, can promote the synthesis of C1 lipase inhibitors, which can be used for C1 lipase inhibitor deficiency, and other treatments for complement component defects are mainly symptomatic treatment.

Prevention of primary immunodeficiency in children

1. Maternal health care: It is known that the occurrence of some immunodeficiency diseases is closely related to embryonic dysplasia. If pregnant women are exposed to radiation, receive certain chemical treatments or have viral infections (especially rubella virus infection), they may be damaged. The fetal immune system, especially in the first trimester, can involve multiple systems including the immune system. Therefore, it is important to strengthen maternal health care, especially in early pregnancy. Pregnant women should avoid radiation, use some chemical drugs with caution, and inject rubella vaccine. Wait, try to prevent viral infections, but also to strengthen the nutrition of pregnant women, and timely treatment of some chronic diseases.

2. Genetic counseling and family surveys: Although most diseases cannot determine the genetic pattern, it is valuable to conduct genetic counseling for diseases with defined genetic patterns. If adults have hereditary immunodeficiency diseases, they will provide the developmental risks of their children. . If a child has an autosomal recessive or sexually linked immunodeficiency disease, tell parents that they are more likely to have a disease in their next child. For immediate family members of patients with antibodies or complement deficiency, antibodies and complement should be examined. Level to determine the family's disease pattern. For some diseases that can be genetically mapped, such as chronic granulomatosis, parents, siblings and their children should be tested for localization. If a patient is found, it should be in him. The family members of her) are examined and the child's children should be carefully observed at the beginning of their birth for any disease.

3. Prenatal diagnosis: Some immunodeficiency diseases can be prenatally diagnosed, such as cultured amniotic fluid cell enzymology can diagnose adenosine deaminase deficiency, nucleoside phosphorylase deficiency and some combined immunodeficiency diseases; Fetal blood cell immunology test can diagnose CGD, X-linked agammaglobulinemia, severe combined immunodeficiency disease, thereby stopping pregnancy and preventing the birth of children. PID is a relatively rare disease, but early diagnosis is accurate and early administration Specific treatment and the provision of genetic counseling (prenatal diagnosis and even intrauterine treatment) are very important.

Patients who have been diagnosed with primary immunodeficiency by primary screening should be genetically diagnosed for diseases with established genetic mutations or deletions, which may be helpful for prenatal diagnosis and genetic counseling.

PID disease registration is being carried out in many countries around the world. Some multinational multi-center research institutions register PID single diseases to understand the global incidence of the disease and the relative incidence of each region and ethnicity. Some genetic mutation sites have been identified. The PID is conducting international cooperation to study the relationship between the genotype and clinical phenotype of the disease. China has not yet established a complete PID disease registration system, so we cannot get our own information on the incidence of PID, and can not carry out the disease genes. Analysis: In 1999, the Immunology Group of the Pediatrics Committee of the Chinese Medical Association proposed to carry out PID registration work nationwide. There are 14 laboratory units in different regions of the country as registration centers. Many pediatricians will be suspicious or confirmed. The PID is sent to the above registration center, and it is hoped that the majority of pediatric workers can actively respond to this work and jointly promote the development of pediatric immunology in China.

Pediatric primary immunodeficiency disease complications Complications meningitis osteomyelitis pneumonia bronchodilation

Repeated infections or opportunistic infections, growth and development delay, common septicemia, meningitis, osteomyelitis and other deep serious infections, gangrenous pyoderma can occur; repeated respiratory infections and pneumonia, bronchiectasis; Anemia and thrombocytopenia, as well as severe post-inoculation reactions, and can be complicated by tumors and autoimmune diseases.

Symptoms of Primary Immunodeficiency in Children Common Symptoms Stomatitis Repeated Infection of Granulocytes Reduces Bacterial Infections Diarrhea Lymph Nodes Liver Splenomegaly Hair Loss Septic Meningitis

The clinical manifestations of PID are extremely complicated due to different causes, but their common performance is very consistent, that is, repeated infection, susceptible to tumors and autoimmune diseases.

1. Repeated and chronic infection: it is the most common clinical manifestation of PID.

(1) Age of infection: about 40% of the disease occurs within 1 year, 40% within 5 years, 15% within 16 years of age, only 5% occurs in adulthood, T cell deficiency and combined immunodeficiency disease The disease occurs shortly after birth; patients with antibody defects, due to antibodies from the mother, are generally susceptible to infection 6 to 12 months after birth, adulthood is mostly common variant immunodeficiency disease (CVID); The main cause of the disease is men (80%), and the majority of women in adulthood (60%).

(2) Infected pathogens: In general, suppurative infections are prone to defects in antibodies, and intracellular pathogens such as Mycobacterium tuberculosis and Salmonella are susceptible to infection by T cells; they are also susceptible to fungal and protozoal infections, and complement component defects are good. Neisseria infection occurs, the pathogen of neutrophil deficiency is often Staphylococcus aureus, the pathogenic bacteria causing PID infection is not very virulence, often opportunistic infection.

(3) The site of infection: the most common respiratory tract, such as repeated or chronic otitis media, sinusitis, combined with membranous inflammation, bronchitis or pneumonia, followed by the gastrointestinal tract, such as chronic enteritis, skin infection can be purulent, abscess or granulation Swelling can also be a systemic infection such as sepsis, sepsis, meningitis and bone and joint infections.

(4) The process of infection: often repeated episodes or prolonged unhealed, the treatment effect is not good, especially the effect of bacteriostatic agents is worse, must use fungicides, the dose of antibacterial drugs should be too large, the course of treatment should be longer, only certain Efficacy.

Although infection is the most common clinical manifestation of PID, not all susceptible people are PID. Some non-immune factors can also cause infection susceptibility. These factors should be excluded when considering the diagnosis of PID. These diseases include systemic Diseases such as diabetes, nephrotic syndrome, uremia, congenital heart disease and sickle cell anemia; local lesions such as urinary calculi, airway foreign bodies, cystic fibrosis, bronchial cilia dysplasia, skull fracture, body foreign body (various catheters and invasive procedures) and severe trauma, in addition, should also exclude a variety of factors that cause SID, such as nutritional disorders, anti-cell drug therapy and tumors.

Children with immunodeficiency disease have increased susceptibility to various pathogens. The main features are: repeated upper respiratory tract infection, severe bacterial infection, persistent infection, poor or no response to anti-infective treatment, and immunodeficiency infection. The characteristics that occur are often manifested by an increase in the number of infections, plus one or more of the following 2 to 7 characteristics:

1 The frequency of infection: The number of infections in children with immunodeficiency is significantly higher than that in normal children.

2 The severity of the infection: the same infection is more severe in immunocompromised children.

3 Duration of infection: Children with immunodeficiency usually last longer than normal children after infection.

4 repeated infections: that is, the symptoms have not completely disappeared after an infection, and the second infection occurs again.

5 dependence on antibiotics increased.

6 After the infection occurs, complications that are rare or extremely serious in normal children can be complicated.

7 Very common pathogen infection, opportunistic infections often occur.

2. Autoimmune diseases and lymphoma: If children with PID die without infection, they may develop autoimmune diseases and tumors with age, especially lymphatic tumors. The incidence of tumors is 10 to 100 times higher than that of normal people. B-cell lymphoma is more common, and cell lymphoma and Hodgkin's disease can also be seen. The autoimmune diseases associated with PID include hemolytic anemia, thrombocytopenic purpura, systemic lupus erythematosus, systemic vasculitis, and cutaneous muscle. Inflammation, immune complex nephritis, type 1 diabetes, immune thyroid dysfunction and arthritis.

3. Other clinical manifestations: often growth retardation or stagnation, rare pathogenic bacteria cause infection, skin lesions (such as rash, seborrheic dermatitis, pyoderma, necrotic abscess, alopecia, eczema, telangiectasia, sputum, etc. ), intractable thrush, diarrhea and malabsorption, difficult to cure sinusitis, mastoiditis, repeated bronchitis, pneumonia, manifestations of autoimmune diseases, lymph nodes, tonsil deficiency, abnormal blood system: aplastic anemia, Hemolytic anemia, neutropenia, thrombocytopenia.

Primary immunodeficiency disease has different degrees of genetic defects. In addition to mainly involving the immune system, other tissues and organs can also be involved. Therefore, clinical signs of primary immunodeficiency disease can occur with various symptoms and signs, some PIDs. There are special manifestations, including thymic hypoplasia with special face, congenital heart disease and hypocalcemia; leukocyte adhesion molecule function defects often appear umbilical cord extension shedding, eczema, bleeding is a unique manifestation of Wiskott-Aldrich syndrome.

4. Rare performance: weight loss, fever, chronic conjunctivitis, periodontitis, lymphadenopathy, hepatosplenomegaly, severe viral disease, chronic liver disease, joint pain or arthritis, chronic encephalitis, repetitive meninges Inflammation, gangrenous pyoderma, cholangitis, hepatitis, severe post-inoculation reaction, bronchiectasis, urinary tract infection, delayed umbilical cord detachment, chronic stomatitis.

5. Family history: Most PIDs have a clear family history. Family history interviews are particularly important when screening suspicious cases and looking for patients with the disease. It may be found that about 1/4 of the families have members who died of early death due to infection. Once a suspicious child is found, a genealogy survey should be conducted. The PID present is occasionally the initiator of the genetic mutation, so there are no similar patients in the family, and the family members of the family have allergic diseases such as asthma, eczema, and autoimmune diseases and tumors. The incidence has also increased significantly.

6. Physical examination: If the infection is severe or recurrent, it may affect the growth and development of the child, weight loss or no increase; may be associated with malnutrition and moderate to mild anemia, B cell deficiency, surrounding lymphoid tissue such as tonsil, adenoid The body and lymph nodes become smaller or absent, and some PIDs appear as systemic lymphadenopathy. Repeated infection can cause hepatosplenomegaly, and other signs of infection can also be seen.

Examination of primary immunodeficiency disease in children

Although the clinical features and symptoms of immunodeficiency disease provide diagnostic clues, they ultimately rely on the detection of immune levels and the correct evaluation of the test results to confirm the diagnosis. Children with clinical manifestations suggesting immunodeficiency should be screened first. Children with no abnormal findings and clinically suggesting immunosuppression should be further tested for immunoassays.

1. Humoral immune function test: The humoral immune response screening test is commonly used for one-way immunodiffusion method to determine serum IgG, IgA and IgM.

(1) The following two points should be noted:

1 difference in normal value: the normal value of serum immunoglobulin varies with age and region, should use the region, preferably the normal value of each unit of the unit, the general serum IgG <2g / L, IgA <50mg / L , IgM <100mg / L can be regarded as a lack.

2 Determination of serum albumin: to exclude hypo-globulinemia due to protein deficiency or loss.

(2) Plasma protein quantification and protein electrophoresis: it is a necessary means to screen for humoral immunodeficiency. According to the absolute and relative values of gamma globulin, it can be judged whether Ig synthesis is reduced. If gamma globulin is less than 6g/L, acetate fiber If the membrane protein electrophoresis gamma globulin is less than 0.125 (12.5%), further Ig quantitative examination should be performed.

(3) Quantification of serum Ig and subclass:

1 Determination of serum Ig content: It is the most commonly used test for detecting B cell function. IgG, IgM and IgA are mostly determined by one-way agar immunodiffusion method, while IgD and IgE are rarely used because of the radioimmunoassay (RLA) or enzyme-linked method. Immunosorbent assay (ELISA), when the total amount of Ig <4g / L or IgG content < 2g / L, it is highly susceptible to infection, serum Ig concentration increases with age, you need to set the normal value of the local age group, If the IgG content is lower than the normal value of 2SD, it should be regarded as abnormal; if the child has repeated bacterial infection and the Ig concentration is normal, the antibody deficiency or IgG subclass defects cannot be excluded, and further examination should be carried out; the normal human serum has very low IgE content. And the normal range of values is extremely wide, so it is more meaningful to determine the specific IgE of an allergen.

2 IgG subclass determination: serum IgG is normal or low, but highly suspected of humoral immunodeficiency, serum IgG subclass can be determined, ELISA or one-way immunodiffusion method can be used to measure each subclass of monoclonal antibodies, Below 2% of the normal value of children of the same age in the region is suspected to be low.

(4) Antibody detection: serum IgG and its subclass values are normal, but highly suspected antibody defects, specific antibodies and antibody responses should be determined, clinically detected:

1 natural antibodies: homologous lectins including blood group antibodies (anti-A and anti-B), phagocytosis, anti-streptolysin "O" (ASO) and antibodies against Escherichia coli, etc., can be used to check IgM Function, for non-AB blood group individuals with normal immune function, anti-Al and B antibody titers at least 6 months after birth are at least 1:8 and 1:4, antibody titers against A and anti-B over 1 year old At least 1:16 and 1:8, respectively, if the titer is lower than normal, suggesting antibody defects.

A. Phagocytosis test <1:10 or 6 months infant homologous hemagglutinin anti-A < 1:8, anti-B < 1:4, suggesting IgM antibody deficiency.

B. Children under 12 years of age are resistant to hemolytic streptococcal hemolysin O (anti-O) < 1:50.

2 After vaccination antibody: After vaccination against measles vaccine, typhoid vaccine and DTP vaccine, the corresponding specific antibodies can be detected separately. If the titer is low, it indicates lack of antibody reaction.

A. Baibaidu vaccine (protein antigen): the specific anti-baibai antibody antibody titer (should have normal control) after 2 weeks of vaccination or 2 weeks after booster immunization For the Sikh test (leather test erythema > 10mm for antibody deficiency).

B. Other protein antigens: Anti-HBV antibodies are determined after vaccination with hepatitis B vaccine. If conditions permit, phage 174 can be used to detect antigen clearance and antibody response (there should be normal controls). The above two vaccines mainly stimulate IgG1 and IgG3 antibody responses.

C. Polysaccharide antigen: commonly used purified polysaccharide antigens are pneumococcal and meningococcal polysaccharides. After 2 weeks of inoculation, serum-specific antibodies are detected, mainly IgG2 components. Infants under 2 years of age have poor IgG2 production ability, and the detection significance is not significant. At this time, the polysaccharide antigen bound to the protein carrier should be inoculated to facilitate the production of the IgG2 antibody.

Live vaccines (such as BCG, polio, measles and rubella) should be banned in patients with suspected primary immunodeficiency.

3 Sikh test: generally after 2 weeks of vaccination or booster injection, the injection of local redness is positive, indicating that IgG antibody is dysfunctional, it should be noted that a small number of children can be negative, especially in repeated trials. after that.

4 If necessary, a new antigen (polysaccharide antigen of Haemophilus influenzae, etc.) can be injected to observe the level of the corresponding antibody.

(5) B cell assay: B cells were counted by immunofluorescence labeling with monoclonal anti-B cell surface antigens CDL9 and CD20 antibodies, and whether B cells were reduced or not, mainly by B cell surface markers, there are many methods for determining B cells. At present, immunofluorescence is mainly used.

1B cell surface antigen and subclass assay: anti-human monoclonal antibody is often used to detect B cell-specific surface antigens (mainly CDL9 and CD20) by fluorescent immunoassay; or B cell membrane surface immunoglobulin (SIg), including SIgG , SIgA, SIgM and SIgD, to distinguish B cell subsets, B cells generally account for 20% to 30% of peripheral blood mononuclear cells, the results should be compared with the normal value of the corresponding age group in this laboratory.

2B cell function test: Peripheral blood mononuclear cells were transformed into Ig-producing plasma cells after being stimulated by Pokeweed (PWM), and the concentration of Ig in the supernatant was measured to evaluate B cell function.

A primary immunodeficiency disease characterized by antibody deficiency.

2. Cellular immune function test

(1) Lymphocyte count, morphology and peripheral blood:

1 Lymphocyte count: It is a simple and direct immunodeficiency test. The number of lymphocytes in peripheral blood is less than 1.2×109/L. It should be considered as T cell defect. It should be reviewed several times to determine whether it is continuously reduced.

2 small lymphocyte reduction: many cell immunodeficiency diseases often appear small lymphocyte reduction, cytoplasmic staining of large lymphocytes, resembling monocytes.

3 anemia, neutrophils and thrombocytopenia: some immunodeficiency patients are prone to varying degrees of anemia, neutrophils and thrombocytopenia, which may be related to autoantibodies.

4 eosinophilia: T cell deficiency can be combined with eosinophilia or mononucleosis, occasionally thrombocytopenia.

(2) T cell function in vivo detection: skin delayed type hypersensitivity (DHT), intradermal injection of 0.1 ml antigen or mitogen causes local skin immune response, which can be used as a screening for T cell-mediated immune response.

1 Delayed skin hypersensitivity (DCH): 0.1 ml of intradermal injection of antigen, observe the reaction at the injection site at 48-72h, if red, swollen, induration diameter 10 ~ 15mm is a positive reaction, greater than 15mm is a strong positive reaction, need At the same time, five kinds of antigens were observed. When they were all negative, they showed defects in T cell function. Commonly used skin antigens were natural antigens such as tuberculin (PPD), streptokinase-chain-directed enzyme (SK-SD), and candida. 3 kinds, of which PPD, SD-SK is more suitable for pediatrics.

2 tuberculin 1:100 ~ 1:1000 old tuberculin, or 10U tuberculin protein pure derivative (PPD), 72h observation, the negative reaction was repeated with 50U.

3 Candida liquid 1:10 ~ 1:100, observed for 48h.

4 Trichophyton liquid 1:30, observed for 48h.

5 mumps: injection of the original solution, antibody reaction (Arthu reaction) was observed for 6-8 hours, and DCH reaction was observed for 48 hours.

6 tetanus, diphtheria toxin 1:100, observed for 48h.

7 Others: Those who do not have the above conditions may also choose phytohemagglutinin (PAH) 66.6mg, streptokinase-chain-directed enzyme 15U, observe for 24h, blush>7mm is positive, PHA skin test does not need prior sensitization. It should be used in pediatrics, but the significance of the current PHA test is still controversial. If the skin test result is negative, it suggests that there may be a low cellular immune function. When judging the results, you should pay attention to:

A. The diagnostic effect of an antigen skin test is small. It is advisable to use at least 2 to 3 antigens for simultaneous examination. It will be more meaningful to consider the results.

B. The clinical significance of the negative skin test should be analyzed in combination with the history of vaccination and previous medical history.

C. The results of neonatal skin test are not completely consistent with cellular immune function, and can be used for X-ray examination. Those with thymography can rule out serious cellular immune defects.

(3) Detection of T lymphocytes in vitro: Peripheral blood T lymphocyte count: Total T cells (CD3), (CD4) and CD8 cells were detected by monoclonal antibody immunofluorescence or enzyme labeling, and CD4 T cells recognized major tissue phases. Capacitive complex (MHC) class II antigens can be further classified into class I or class II helper T cells (Th1 CD3 or Th2). CD8 T cells recognize MHC class I antigens and are mainly involved in cell-mediated immunity (cytotoxic T cells). Abnormal numbers of CD4/CD8 T cells can lead to immunodeficiency or autoimmune diseases, and CDL6 surface markers are measured to count natural killer cells (NK). In patients with suspected high IgM syndrome, CD40 ligand expression was detected after activation of T cells with phorbol fatty acid (PMA) and ionomycin.

1T cells and their subpopulations: T cell surface antigens were detected by immunofluorescent antibody technology or flow cytometry using monoclonal antibodies to the CD system, reflecting the ratio of T cells to T subpopulations.

AT lymphocyte count: Mature T cells have CD2 and CD3 on the surface, and T cells can be counted using anti-CD2 or CD3 mAb.

BT cell subset count: Two large T cell subsets can be counted with anti-CD4 and CD8 monoclonal antibodies and the ratio is calculated. In normal human peripheral blood, T cells account for about 70% of mononuclear cells, and the CD4/CD8 ratio is 1.7±0.4. .

2 In vitro T cell function test: available polyclonal mitogen PHA, Pokeweed (PWM) and Concanavalin A (conA), other antigens (PPD), fungi, streptokinase, tetanus toxoid, diphtheria toxoid) , superantigens (such as toxic shock syndrome toxins), allogeneic cells (mixed lymphocyte culture) and anti-T cell surface monoclonal antibodies (CD3, CD2, CD28 and CD43 antibodies) involved in the signaling system stimulate T cells, observe The following functions: A. Activation function: IL-2R (CD25), transferrin receptor (CD71) and MHC class II molecules were expressed by immunofluorescence with monoclonal antibodies. B. Proliferative function: Morphological observation of lymphoblastic transformation or 3H incorporation to observe the proliferation index. C. Differentiation function: The activity of cytokines such as IL-2, IL-4, IL-6 and IFN- in the culture supernatant should be determined. The above test should be set as the control group, the primary immunodeficiency disease of T cell deficiency. .

Detecting the responsiveness of T cells to stimulating factors in vitro, ie, the ability to divide, proliferate, and transform into mother cells. The stimulating factors include mitogens (PHA, ConA), (PPD, white candida, etc.) antigens, targeting T cells.

A.T()<3HDNA(CPM)(SI)SI<3T

B.(IFN-)(IL)IL-2IFN-T

C.(IL-2)

D.TT

3.

(1)4×109/LChédiak-Higashi()

(2)CDL4(NBT)CDL1abcNBT

A.Chédiak-Higashi

B.RebuckBoyden

Quie120min95%10%

NBTNBT10%<1%

NBT(-)

(3)Howell-Jolly

4.

(1)(CH50 )(C1qrsC2C9)(DHIC1)(9)

C3(C3)C1qC2C4C5C7C3 C4C3bC4bC57

(2)C3C5

5. Other inspections

(1)(ESR)ESR;Howell-Jolly;Wiskott-Aldrich<1×109/L(SCID)SCIDWiskott-Aldrick

(2)

57;SCID

IgACVIDSIgAD

BBruton(5)

(3)SCIDT(ADA)(PNP);SCIDTMHC()Wiskott-Aldrich(MHC)()

95%(402000mg/L)-6-

6.

XB

X6

diagnosis

1.Modell

Modell10

(1)18

(2)12

(3)2

(4)12

(5)

(6)

(7)1

(8)

(9)2

(10)

2.199511

(1);6;;(), (-A)()(EB )()

(2)

PIDPIDPID310PID

(3)(Ig)80%PIDIgIg<6g/LIgG<4g/LIg<4g/LIgG<2g/LIgGIgGIgEIgB

(4)80%TT(26)×109/L2×109/LT1.5×109/LT

(5)Chédiak-Higashi

(6)XT

(7)(delayed leptochroa test)Th12472h

25Th1Th1T(PHA) 66.6mg/ml0.1ml(DNCB)

(8)(nitroblue tetrazolium testNBT)NBTNBT8%14%1%G-6-PD

NBT

NBTNBT90%1%

2NBTNBTNBT

(9)CH50C3C4CH50CH5050100U/mlC350%C4C3C35701160mg /L135301310mg/L316201800mg/L1107701950mg/LC470230mg/L1370270mg/L31070400mg/L

PIDDNA

Differential diagnosis

SID(PID)

1.PID;SIDPID(immunocompromise)

2.PIDSID

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