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Hemolytic disease of New born IgG sub Class evlauation

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Hemolytic disease of the newborn

Hemolytic disease of the new-born (HDN) is a disease in which new-born babies show an anemia caused by breakdown of the erythrocytes. This is triggered by maternal (IgG) antibodies, which have passes the placental barrier and bind to the foetal erythrocytes. During pregnancy, but most pronounced during childbirth, erythrocytes exchange between foetus and mother. If the foetal erythrocytes express antigens which are not present on the maternal erythrocytes (e.g. Rhesus D antigen), antibodies directed against these blood groups can be produced by the mother.
Antibodies to blood group antigens show a more or less IgG subclass-distinct profile. The influence of the IgG subclass of anti-Rhesus D antibodies on the severity of hemolytic disease of the newborn has been examined by many groups (99,100,101,102). In the majority of samples tested, both IgG1 and IgG3 antibodies were detected and the hemolytic disease was more severe than when only IgG1 was present. The significance of IgG3 antibodies is controversial. Some authors have suggested that IgG3 is always associated with overt hemolysis, but others could not confirm this. Blood group antibodies of the IgG4 subclass, in contrast to those of IgG1, IgG2 and IgG3 subclasses, are known not to cause clinical problems (hemolysis), which finding is mainly explained by the inability of such antibodies to activate complement(22,103,104,105).The determination of IgG subclasses is indicated especially when there is a clear discrepancy between serological findings and signs of increased red cell destruction in vivo (106).

4.5 Indications for measuring IgG subclass levels

As already mentioned in the previous sections, several studies indicate that (selective) IgG subclass deficiencies may be associated with disease. Specific examples are: bronchiectasis and severe, recurrent stages of otitis media, sinusitis, pneumonia and bronchitis. The possibility of an IgG subclass deficiency should be considered in all children with recurrent infections and chronic obstructive bronchitis. The association between IgG2 deficiency and severe recurrent infections of the respiratory tract in young children, caused by encapsulated bacteria, have led to an increasing demand for the determination of IgG subclasses in sera from children. However, it should be kept in mind that IgG subclass deficiencies in children may be transient. The levels of IgG2 increase relatively late in childhood. Thus, when low IgG2 levels are found in children below the age of 2-3 years, it is advisable to monitor this level in the course of time, since it may be due to a temporary maturation block. Obviously, IgG subclass deficiencies may also occur in all patients at risk for infections due to immunodeficiency, such as occurs e.g. in haematopoietic stem cell transplantation.

In general, IgG subclass levels should be measured whenever the total IgG level is decreased. However, and IgG subclass deficiency is not excluded by a normal or even high total IgG concentration (62). Therefore, it is essential to measure individual IgG subclass levels (107). A correct diagnosis is essential in choosing the appropriate therapy (108). There are several specific disease conditions in which measurement of IgG subclasses is recommended:

- Several specific infections, such as meningitis caused by pneumococci, Haemophilus influenzae (B) and meningococci or osteomyelitis and severe pneumonia;
- Recurrent purulent infections of the upper and lower respiratory tract (it is advisable to assess the actual causative agent(s) by means of serology and culture of the micro-organisms in vitro);
- Bronchiectasias and/or purulent infections of unclear etiology, such as cystic fibrosis, immotile cilia syndrome (Kartagener syndrome), or a history of earlier infections like measles-pneumonia;
- IgA-deficiency associated with infectious disease (pneumonia, sinusitis, etc.);
- Diseases mentioned in chapters 4.2 and 4.4.

4.5.1 Assessment of immune status

The determination of IgG subclass levels is included in the routine laboratory tests for the assessment of the immune status. It is used as a parameter of humoral immunity. For diagnostic testing of pediatric and adult patients with recurrent infections in whom an immunodeficiency is suspected, the following protocol has been developed by the Netherlands Working Party for Immunodeficiencies (109). A characteristic feature of this protocol for the assessment of immunological competence is a graduation in stages of tests with more or less increasing complexity.

A. Patient's history

-Infections: Localization, frequency, duration, reaction to antibiotic therapy, nature of the infectious micro-organism(s): viruses, bacteria, fungi, protozoa
-Allergy: asthma, eczema, diarrhea
-Family: early deaths of other children, occurrence of severe or unusual infections, malignancies, auto-immune diseases

B. Physical examination

- assessment of sites of infection (ear/nose/throat, lungs, abdomen, urogenital, skin)
- swelling or absence of lymphoid tissue (lymph nodes, adenoid, tonsils, spleen)

C. Non-specific immunity

- differential leucocyte count (basophils, eosinophils, neutrophils, lymphocytes, monocytes)
- haemolytic complement (classical and alternative pathway: CH50 and AP50
- opsonic activity of patient's serum
-phagocytic activity of patient's granulocytes

D. Specific immunity

- Specific antibody responses before and after vaccination (Diphtheria/Tetanus/Polio, Haemophilus influenzae B conjugate, Pneumovax, Meningovax type A/C). Since patients with IgG subclass deficiencies frequently suffer from infections with pneumococci and Haemophilus bacteria, it is important to measure specific antibodies against these micro-organisms, before and after vaccination, using the polysaccharide- or conjugate vaccines now commercially available.

4.5.2 Therapeutic considerations

For individuals with IgG subclass deficiencies who also develop clinical symptoms (e.g. recurrent infections), treatment should be considered. Treatment of such patients will generally consist of anti-microbial therapy, immunoglobulin substitution and vaccinations.

Conservative treatment, comprising early antibiotics treatment during infections, prophylactic antibiotic treatment in selected individuals and supportive symptomatic therapy should be the first line of treatment, sometimes supplemented with intravenous immunoglobulin. In patients with primary specific immunodeficiency who have significantly diminished serum IgG levels and/or demonstrated defects in antibody production, intravenous immunoglobulin replacement therapy is currently most often used, since administration of immunoglobulins will reduce the incidence of bacterial and viral infections.
Patients with selective IgG subclass deficiency may benefit from IgG replacement (WHO-report)(110).

The maturation of an immune response can be enhanced by repeated vaccination. Vaccination with Diphtheria/Tetanus/Polio proteins (T cell-dependent antigens) from the age of three months is generally performed. Active immunization against polysaccharide antigens (T cell-independent antigens) is ineffective until about the age of 18 months, because of the slow ontogeny of the anti-polysaccharide immune response. By coupling the polysaccharide antigens to protein carriers conjugate-vaccines), the T cell-independent response is changed into a T cell-dependent one, leading to an effective response against polysaccharide antigens in young children (111, 112, 113, 114). In IgG2-deficient patients, only a marginal compensating mechanism exists, as illustrated by the impaired anti-polysaccharide response in all other immunoglobulin isotypes. This poor responsiveness can be partly bypassed by using conjugate-vaccines.
Nevertheless, it should be kept in mind that active vaccination procedures may fail, due to a deficient humoral immunity.

Hemolytic disease , newborn ,gG1, IgG2 , IgG3 subclasses


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