Application of human immunoglobulin in immunodeficiency

Application of human immunoglobulin in immunodeficiency.   Immunoglobulin (lg) is an antibody produced by plasma cells differentiated by B cells. Ig molecules have a unique structure and can specifically recognize antigenic determinants.

Ig preparations are prepared from the mixed plasma of many healthy blood donors (>1000 persons per batch), separated and purified by low-temperature ethanol protein separation method or other approved separation methods, and processed by virus removal and inactivation. Ig preparations contain a large number of different antibody libraries and are therefore widely used in various immune system diseases.

Primary immunodeficiency disease

Primary immunodeficiency (PID) affects different components of the innate and adaptive immune system such as macrophages, natural killer cells, dendritic cells, neutrophils, complement proteins, B lymphocytes and T lymphocytes. As a type of genetic disease, primary immunodeficiency disease can occur alone or as part of a clinical syndrome, mostly in infancy or childhood, and the total incidence is about 1/1200.

Agammaglobulinemia

Agammaglobulinemia is characterized by a lack of B lymphocytes in the blood and bone marrow, resulting in extremely low serum antibody levels. Can be divided into X-linked, X-linked with growth hormone deficiency and autosomal recessive agammaglobulinemia, the former accounted for 85%.

The most common symptom caused by agammaglobulinemia is repeated respiratory infections. The pathogens include Streptococcus pneumoniae, Haemophilus influenzae type B, Streptococcus pyogenes, and Pseudomonas.

The normal range of adult IgG concentration is 7 to 16.6 g/L. Through IgG replacement therapy, maintaining the trough IgG concentration (the IgG level in the peripheral blood before IVIG infusion) above 5 g/L can prevent serious bacterial infections. Studies have shown that for every 1 g/L increase in IgG concentration, the incidence of pneumonia decreases by 27%. The risk of pneumonia in patients with a trough lgG concentration of 10 g/L is one-fifth that of patients with 5 g/L.

Hypogammaglobulinemia

Hypogammaglobulinemia occurs when the level of Ig in the serum decreases or the lack of IgG antibody response to antigen challenge is low. Primary hypogammaglobulinemia affects young children and adults, including combined immunodeficiency diseases such as Wiskott-Aldrich syndrome and high IgM syndrome.

Common variant immunodeficiency (CVID) is the most common primary disease causing hypogammaglobulinemia. Diagnostic criteria: low IgG level measured at least twice in 3 weeks (no need to repeat the measurement when the IgG level is 1-3 g/L), low IgM and/or IgA, and at least one type of T cell dependent or independent antigen The response is low, and other types of hypogammaglobulinemia are excluded. Patients may also have a variety of T cell abnormalities.

CVID usually has no genetic background, although mutations in CD81, CD19, CD20, CD21, inducible costimulatory factors, transmembrane activators, calcium regulation and cyclophilin ligand interaction factors, and B cell activating factor have been found in the CVID patient cohort. The clinical manifestations of CVID include infections (especially infections of the respiratory tract, sinuses, and gastrointestinal tract), inflammatory diseases, autoimmune diseases, and increased risk of cancer and lymphoma.

Ig replacement therapy is effective in patients with repeated bacterial infections and low serum Ig levels. The preventive IgG replacement dose is 0.2 g/kg/month to 1.2 g/kg/month, and the phenotype of CVID is an important factor in determining the Ig dose. Compared with patients with malignant tumors of the lymphatic system, patients with bowel disease, cytopenias and polyclonal lymphocyte proliferation require larger doses of Ig. 

Lack of specific antibodies

Specific antibody deficiency (SAD), also known as selective antibody deficiency, is a patient with normal Ig levels but impaired production of specific antibodies. SAD patients have normal levels of IgA, IgM, total IgG and IgG subclasses; however, they also have repeated infections after vaccination, and their immune response to polysaccharide antigens is low.

Antibiotics are the first-line treatment for infections; abnormal sinus or lung imaging, increased C-reactive protein and erythrocyte sedimentation rate are indications for Ig replacement therapy. In addition, Ig replacement therapy needs to be initiated for patients with recurrent and refractory otitis media with permanent hearing loss, bronchiectasis, recurrent infections, and antibiotic prophylaxis.

Secondary immunodeficiency

Secondary immunodeficiency (SID) is the immune system damage caused by non-genetic factors, mostly caused by serious infections, especially infections that directly invade the immune system, malignant tumors, the application of immunosuppressants, radiation therapy, and chemotherapy. . Ig replacement therapy has been used in a variety of diseases that can lead to secondary humoral immunity, including hematological malignancies, HIV infection in children, premature infants, old age, hypogammaglobulinemia associated with organ or bone marrow transplantation, and receiving Patients treated with B cell depleting agents.

Chronic lymphocytic leukemia

Hypogammaglobulinemia is a common complication of chronic lymphocytic leukemia (CLL). Hypogammaglobulinemia and (or) infections caused by advanced disease account for 30%-50% of CLL deaths.

For patients with CLL with recurrent severe bacterial infections whose antibody levels are below the protective level after receiving diphtheria, tetanus or pneumococcal vaccines, clinicians may consider initiating alternative Ig therapy. It should be emphasized that the choice of Ig therapy for patients should be based on confirmed antibody production defects, and pure hypogammaglobulinemia is not an indication for initiating treatment.

Multiple myeloma

Infection is the main cause of death in patients with multiple myeloma (MM). 45% of early deaths (within 6 months) in patients with MM are caused by infection. A recent study of 9253 patients found that the risk of any infection in MM patients was 7 times that of the control group.

The results of multiple trials have shown that the incidence of major infections is significantly reduced in MM patients receiving IgG therapy. For patients with MM with hypogammaglobulinemia and confirmed lgG deficiency, IVIG replacement therapy should be considered based on individual conditions.

Summary of the application of immunoglobulin in primary and secondary immunodeficiency

Summary

PID, which is characterized by decreased or dysfunctional B cells and/or IgG, is the main indication for IgG replacement therapy. Before starting treatment, the baseline Ig and specific antibody levels of previous vaccination should be recorded. 

The basic regimen of IgG replacement therapy is IVIG 0.4-0.6 g/kg every 3 to 4 weeks, maintaining a trough IgG concentration above 5-6 g/L. 

The efficacy of IVIG in SID is not yet clear, but related research and clinical applications are also extensive. 

The administration of IVIG should pay attention to the principle of individualization, adjust according to factors such as disease conditions and clinical reactions, and pay attention to monitoring serious adverse reactions during the treatment.