Primary immunodeficiency diseases (PID) are congenital or genetic disorders characterized by the deficiency or dysfunction of immune factors, including specific cellular and humoral immune deficiencies mediated by T and B cells, as well as non-specific immune dysfunction caused by abnormalities in complement system activation and phagocyte system function. The pathogenesis is related to abnormalities in the development, differentiation, or metabolism of immunocompetent cells or congenital genetic defects in these cells. Clinically, these diseases are marked by recurrent severe infections and high mortality rates. However, in recent years, immunotherapy, immune factor replacement therapy, and hematopoietic stem cell transplantation have played a role in improving prognosis.

bubble_chart Type

1. Specific Immunodeficiency Diseases

(1) Humoral Immunodeficiency Diseases

1. Congenital X-linked Agammaglobulinemia
2. Transient Hypogammaglobulinemia of Infancy
3. Selective Immunoglobulin Deficiency: (1) Selective IgA Deficiency (2) Selective IgG Deficiency
4. Common Variable Immunodeficiency (CVID)

(2) Cellular Immunodeficiency Diseases

1. Purine Nucleoside Phosphorylase Deficiency
2. Thymic Hypoplasia (DiGeorge Syndrome)
3. Cartilage-Hair Hypoplasia

1. Severe Combined Immunodeficiency Disease (SCID)
   1. Swiss-type Agammaglobulinemia (Swiss)
   2. Adenosine Deaminase Deficiency
   3. SCID with Immunoglobulin Synthesis Defect (Nezelof)
   4. SCID with Leukopenia
2. Other Related Diseases
   1. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)
   2. Ataxia-Telangiectasia
   3. Chronic Mucocutaneous Candidiasis

(1) Phagocytic Function Defects

1. Chemotaxis Defect
2. Phagocytosis Defect
3. Bactericidal Function Defect

bubble_chart Clinical Manifestations

1. Common manifestations of primary immunodeficiency diseases
   1. May have a family history.
   2. History of recurrent severe infections after birth.
   3. Prone to autoimmune diseases.
   4. Some cases may be complicated by lymphoid tumors.
   5. May exhibit delayed growth and development.
2. Special manifestations of different immunodeficiency diseases (discussed later).

bubble_chart Auxiliary Examination

1. Immune Function Testing
   1. Cellular Immunodeficiency Diseases:
      1. Low absolute lymphocyte count;
      2. Abnormal delayed-type skin hypersensitivity test, lymphocyte transformation test, macrophage migration inhibition test, abnormal T-cell subsets, etc.
   2. Humoral Immunodeficiency:
      1. Serum protein electrophoresis shows lack of globulin;
      2. Immunoglobulin assay reveals deficiencies in IgG, IgM, IgA;
      3. Decreased titers of isoagglutinins such as anti-A and anti-B;
      4. Low titers of specific antibodies like antistreptolysin O;
      5. Reduced B-lymphocyte count.
   3. Granulocyte Function Defects:
      1. Decreased absolute granulocyte count;
      2. Abnormal granulocyte chemotaxis test, granulocyte phagocytic function assay, bactericidal activity, and nitroblue tetrazolium test.
2. X-ray examination showing absence of thymic shadow in infancy suggests cellular immunodeficiency or combined immunodeficiency disease. Absence of thymic and nasopharyngeal adenoid shadows is seen in Swiss-type agammaglobulinemia.
3. Lymph node biopsy revealing thin cortex, lack of plasma cells, absence of germinal centers, and few lymphoid follicles suggests humoral immunodeficiency. Absence of lymphocytes in the cortical paracortex indicates cellular immunodeficiency.
4. Peripheral blood erythrocyte adenosine deaminase and purine nucleoside phosphorylase assays aid in the diagnosis of enzyme deficiency diseases.

bubble_chart Diagnosis

Diagnostic Key Points of Common Primary Immunodeficiency Diseases:

1. Congenital X-linked Agammaglobulinemia: Occurs only in boys, typically manifesting between 4 to 12 months after birth. Frequent pyogenic infections are common. Physical examination reveals absent or very small lymph nodes and tonsils. Thymus development is normal. Serum immunoglobulins are significantly reduced, with IgG often below 1.0 g/L, and IgA and IgM often undetectable. Plasma protein electrophoresis shows extremely low gamma globulin levels, but cellular immune function is normal. Diagnosis requires differentiation from transient hypogammaglobulinemia of infancy, a self-limiting condition affecting both sexes, where susceptibility to Gram-positive coccal infections occurs before ages 2–4 due to temporary insufficient immunoglobulin production. Total serum IgG, IgA, and IgM are usually below 4.0 g/L, with inadequate specific antibody formation in response to diphtheria and toxoids. Rectal mucosal lamina propria lymph node biopsy may reveal plasma cells, aiding differentiation.
2. Severe Combined Immunodeficiency (SCID): A hereditary sexually transmitted disease caused by defects in both humoral and cellular immunity. Shortly after birth, severe recurrent bacterial, viral, or fungal infections occur, often accompanied by chronic diarrhea leading to malnutrition. X-rays show absence of thymic shadow and adenoid tissue in the nasopharynx. Serum immunoglobulins are markedly reduced, with poor specific antibody response post-vaccination. Delayed-type hypersensitivity is typically negative, lymphocyte transformation rate is very low, peripheral blood lymphocyte count is minimal, and the bone marrow lacks plasma cells and lymphocytes. Pathological features include lymphocyte and plasma cell deficiency in lymphoid tissues and thymic hypoplasia.
3. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome, WAS): An X-linked recessive disorder characterized by bleeding manifestations from early childhood, severe eczema, recurrent infections, and thrombocytopenia. Serum IgG levels are normal, IgM is often reduced, and isoagglutinin titers are low. Cellular immune function may be normal or show incomplete T-cell immunodeficiency.
4. Ataxia-Telangiectasia: After age 8, telangiectasia appears on the ocular conjunctiva, nasal bridge, and skin of the limbs, accompanied by progressive cerebellar ataxia, developmental delay, and susceptibility to recurrent infections. Abnormalities in cellular and/or humoral immunity may be present.
5. Chronic Granulomatous Disease: Recurrent and chronic pyogenic infections with localized granuloma formation occur in infancy, commonly affecting the skin and lungs, and may involve hepatosplenomegaly. Leukocytosis, elevated serum IgG, normal cellular immune function, and impaired granulocyte bactericidal activity are observed.

bubble_chart Treatment Measures

(1) General Treatment

1. Strengthen nursing care and actively prevent and treat various infections, with special attention to preventing and treating infections by attenuated pathogens. Acyclovir can be used to prevent and treat infections by herpesvirus, cytomegalovirus, and other viral infections; ribavirin can be used to treat respiratory syncytial virus, parainfluenza virus, and other infections. SMZco can be used to prevent and treat conditions such as Pneumocystis carinii pneumonia.
2. Symptomatic treatment.
3. For patients with cellular immunodeficiency and combined immunodeficiency, live vaccines and bacterial vaccines (e.g., measles attenuated live vaccine, BCG, etc.) are contraindicated. For those with normal antibody synthesis function, inactivated vaccines (e.g., inactivated polio vaccine, etc.) can be used.

(2) Replacement Therapy

1. Gamma globulin preparations can be used to treat IgG deficiency. IVIG therapy is effective as a replacement treatment for various antibody deficiencies and combined immunodeficiency diseases (e.g., X-linked agammaglobulinemia, common variable immunodeficiency, transient hypogammaglobulinemia of infancy, SLID, WAS, etc.), but it cannot restore immune function and has certain side effects. After injecting 100 mg/kg of gamma globulin, serum IgG levels can increase by 100 mg/dl, with a half-life of 25–30 days. Generally, the initial injection is 0.2–0.3 g/kg, with a total dose not exceeding 30 ml per administration, given intramuscularly. Subsequently, 0.1 g/kg is injected intramuscularly monthly, with each dose not exceeding 20 ml.
2. Fresh plasma can be used to treat various humoral immunodeficiency diseases. The dosage is 10–15 ml/kg every 3–4 weeks.
3. For treating neutrophil function defects with severe infections, single-donor leukocytes, fresh leukocyte suspensions, or fresh whole blood can be transfused.
4. For treating adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency, red blood cell transfusions can be administered. Blood products must be irradiated before transfusion to prevent post-transfusion GVHD.
5. Thymosin can be used to treat thymic hypoplasia.
6. Transfer factor is used to treat cellular immunodeficiency diseases, with partial effectiveness in some cases. Treatment with IFN-γ can reduce the risk of certain severe infections.

This can restore immune function in some patients. For example, bone marrow transplantation from a matched related donor for SLID or Wiskott-Aldrich syndrome can partially restore immune function in affected children, with long-term survival rates reaching 80–90%. Transplantation from a haploidentical related donor or a matched unrelated donor can achieve survival rates of over 60%. There are also reports of effective treatment for thymic hypoplasia using fetal thymus transplantation.

bubble_chart Prevention

Genetic counseling for couples of childbearing age.