Effect of Anti-Epileptic Drugs on Serum Level of IgG Subclasses

Objective

There are some controversial studies on effects of anti-epileptic drugs (AEDs) on serum IgG subclasses; however, the role of these medications is still unclear. The aim of this study was evaluation the effects of anti-epileptic drugs on serum concentration of IgG and its subclasses

Methods

Serum IgG and IgG subclasses of 61 newly diagnosed epileptic patients were measured at the beginning of monotherapy with carbamazepine, sodium valproate, and phenobarbital, and 6 months later. Measurement of IgG and its subclasses was performed using nephlometry and ELISA techniques, respectively.

Findings

Reduction of at least one IgG subclass was found in 6 patients 6 months after treatment with AEDs. Among 27 patients receiving carbamazepine, decrease in at least one serum IgG subclass level was found in 5 patients. Among 20 patients using sodium valproate, only one patient showed decrease in IgG2 subclass. None of the 14 patients using phenobarbital revealed significant decrease in IgG subclasses. No infection was seen in the patients with reduction of subclasses.

Conclusion

Although in our study, children with selective IgG subclass deficiency were asymptomatic, assessment of serum immunoglobulin levels could be recommended at starting the administration of AEDs and in serial intervals afterward in epileptic patients.     

IgG SUBCLASS LEVELS IN INFANCY AND CHILDHOOD

Abstract. Oxelius, V. (Department of Paediatrics, University Hospital, Lund, Sweden). IgG subclass levels in infancy and childhood. Acta Paediatr Scand, 68: 23, 1979.—The concentrations of IgG1, IgG2, IgG3 and IgG4 were determined by electroimmunoassay in 10 pairs of maternal and cord sera and in sera of 162 healthy children, aged 6 weeks to 15 years. Specific rabbit antisera against the IgG subclasses were used. The content of the normal serum pool WHO 67/97 was used as reference. The mean value, standard deviation and normal range of each IgG subclass were calculated for each age group and compared with the adult values. All IgG subclasses were present in cord serum except for IgG4 in those cases where also the maternal serum lacked demonstrable IgG4. The IgG subclasses followed the pattern of total IgG with a fall during the first 3–6 months and a subsequent gradual rise with age. The IgG1 and IgG3 levels rose faster with age than IgG2 and IgG4. Adult levels were not reached before puberty. No IgG4 was detectable in 12–21% of the children above 7 years of age.     

IgG subclasses in wheezing infants

The wheezing infant is a common but difficult patient to approach diagnostically. The prevalence of IgG subclass antibody deficiency in wheezing infants is still controversial. We studied serum concentration of IgG subclasses in 38 wheezing infants (aged 6–24 months who had not received systemic steroids before investigation) and in 30 healthy age matched control (aged 6–24 months). The prevalence of one or more IgG subclass deficiency was 31.6% in wheezing infants and 26.7% in controls. There was no significant difference in prevalence of IgG subclass deficiency between patients and controls (p>0.05). The mean concentration of IgG subclasses in patients were compared with controls. There was no significant difference in mean serum concentration of IgG1, G2 and G3 subclasses. But there was a trend towards higher concentrations of IgG4 in wheezing infants and this difference for IgG4 was significant (p<0.01). However, IgG subclass deficiency was found in 25% and 36.4% of wheezing infants who had experienced from two to four and five or more wheezing episodes in two years, respectively (p>0.05). These findings suggest that wheezing in infancy is not associated with IgG subclass deficiency and in wheezing infants low IgG subclass levels do not increase the frequency of wheezing.     

Increased IgG2 and IgG3 Concentration Is Associated with Advanced Pseudomonas Aeruginosa Infection and Poor Pulmonary Function in Cystic Fibrosis

ABSTRACT. The concentrations of IgG subclass immunoglobulins were determined by radial immunodiffusion in serum from 126 patients with cystic fibrosis (CF). The results were compared to values from age-matched healthy children and adults and correlated to patients age, duration of chronic Pseudomonas aeruginosa infection and lung function parameters. Fifty-two percent of the patients had an elevated concentration of at least one of the IgG subclasses; IgG1 28%, IgG2 16%, IgG3 18% and IgG4 48%. There was significant correlation between elevated serum levels of IgG2, and to a lesser extent IgG3, with decreased lung function (for FEV₁; p =0.0001, and p =0.001 respectively) and high levels of antipseudomonas precipitins ( p =0.008, and p =0.002). A similar correlation was not found for IgG1 and IgG4. IgG subclasses vary in their ability to promote phagocytosis and to activate complement and it is possible that individual differences in the IgG subclass pattern could explain the variable course of this disease.     

IgG subclasses in children with recurrent respiratory tract infections in an allergy practice

Isolated or combined deficiencies of immunoglobulin G (IgG) subclasses have been recognized in children with recurrent infections. In our allergy practice, there are a subset of children with recurrent respiratory tract infections. To investigate the presence of immunoglobulin G subclass deficiency (IgGSD), 60 children with atopy and 14 children without atopy suffering from recurrent respiratory tract infections were studied in an attempt to determine whether atopy is associated with a certain IgG subclass pattern. Ten atopic children were found to have isolated or combined IgG subclass deficiencies: one with IgG1, two with IgG2, four with IgG3 and three children had IgG2–IgG3. Neither IgG subclass concentration nor the frequency of children with high or low IgG subclasses showed any difference between atopic and non-atopic groups. Except for a week correlation with IgG3, no correlation existed between IgE and other IgG subclasses. It was concluded that childhood respiratory diseases complicated by recurrent respiratory tract infections may be associated with IgG subclass deficiencies. Although there have been reports noting some IgG subclass patterns in atopic disorders, in the present study, no distinctive feature between atopics and non-atopics with respect to IgG subclass concentrations and patterns was observed.     

Comparison of IgG subclasses in foetal serum, maternal serum at delivery and milk in IgA-deficient and control women

Immunoglobulin G subclass concentrations were measured in paired foetal (cord) and maternal serum specimens at delivery from 27 IgA-deficient (serum IgA < 0.01 g/l) and 15 control women. IgA-deficient women had significantly higher serum IgGl and IgG3 concentrations than control women but 2 of the group had concomitant IgG2/IgG4 deficiency and a further 12 had low IgG4 concentrations (serum IgG4 < 0.025 g/l). Foetal serum also had significantly higher IgGl concentrations than control foetal serum but lower IgG2 and IgG4 levels. Concentrations of IgG subclasses and IgM were measured in breast milk collected on the fifth day postpartum from 19 of these IgA-deficient and 18 control women. Between-group differences in IgG subclass levels resembled those in serum. Compared with serum, proportionally less IgG3 was present in milk in both groups although the contribution of IgG3 to total IgG was not less than that of IgG4. Slightly higher IgM was found in milk from the IgA-deficient mothers.     

IgG and IgG subclasses deficiency in children undergoing continuous ambulatory peritoneal dialysis and its provocative factors

BACKGROUND: Low levels of serum IgG or IgG subclasses may be responsible for the defective peritoneal defense and for peritonitis attacks in continuous ambulatory peritoneal dialysis (CAPD) children. Malnutrition, peritoneal loss or frequent peritonitis may lead to IgG or IgG subclasses deficiency. METHODS: Levels of IgG subclasses were determined in 12 children undergoing CAPD treatment. Radial immunodiffusion technique was used for determination. Patients were aged from 6 to 16 years (mean age 12.3 years) and had been on CAPD for 11-26 months (mean duration 19.4 months). We evaluated whether IgG and IgG subclasses deficiency are related to malnutrition, the peritonitis rate and the duration of CAPD using the SPSS program. RESULTS: Serum total IgG levels were found to be low in eight out of 12 patients. Eight patients showed low levels of IgG1, four patients IgG2, one patient IgG3 and three patients IgG4. Total IgG values were found to be positively correlated to malnutrition status, peritonitis rate and duration of CAPD. The IgG2 values were found to be related to the duration of CAPD. The IgG4 values were found to be correlated to the peritonitis rates. CONCLUSIONS: The IgG and IgG subclasses deficiency may develop in children while on CAPD treatment. Periodical determinations of either serum IgG or the subclasses may be useful in the follow-up of these patients.     

Placental transfer of IgG subclasses in a Japanese population

BACKGROUND: Maternal immunoglobulin G (IgG), transferred across the placenta to the fetus during intrauterine life, is an important component of the neonatal immunological defence mechanisms against infection. There is controversy with respect to differences in placental transfer of the different IgG subclasses, and no definite data are available on a Japanese population. Therefore, we investigated placental transfer of IgG subclasses in a Japanese population. METHODS: A total of 228 matched pairs of cord and maternal serum samples (20-42 weeks gestation) were assayed for each IgG subclass by an enzyme-linked immunosorbent assay. RESULTS: The mean values and hierarchy of cord/maternal concentration ratios of IgG subclasses at 40 weeks gestation were as follows: IgG1(1.47) > IgG3(1.17) = IgG4(1.15) > IgG2(0.80). The cord/maternal concentration ratios of all IgG subclasses were positively correlated to gestational age. The mean ratios for IgG1 and IgG4 nearly reached a plateau at 39 and 37 weeks gestation, respectively, while those for IgG2 and IgG3 increased until 41 weeks gestation. The ratios of all IgG subclasses for full-term deliveries were reciprocally correlated to the respective maternal IgG subclass serum levels. CONCLUSIONS: The results suggest that although all four IgG subclasses are actively transferred across the placenta, the efficiency of their transfer ranks in the order IgG1 > IgG3 = IgG4 > IgG2. The different results as to placental transfer of IgG subclasses in the literature might be due, at least in part, to different maternal IgG subclass serum levels in the populations studied.     

Serum IgG subclass concentrations in healthy subjects at different age: Age normal percentile charts

IgG subclass levels were determined in 448 normal children from 6 months to 18 years of age and in 141 healthy adults by radial immunodiffusion using monoclonal antibodies. Age-normal percentile values were calculated for each year of age up to 18 years for IgG1, IgG2, IgG3 and in adults for all four subclasses. The broad spread of IgG4 values in children did not permit calculation of reference values.     

IgG subclass deficiency

The different biological properties of human IgG subclasses make each subclass unique in its functional role in either resistance to infection, autoimmune diseases or allergy. Not only are there marked differences in the relative concentrations of IgG subclasses in serum (IgG₁ > IgG₂ > IgG₃/IgG₄) but the distribution of the antibody responses in the 4 subclasses of IgG can vary markedly depending on the nature of the antigen, the type of infection, the degree of antigen exposure, the immunization regimens, the age of individual, the immune disorder and the allotype of the individual. Measurement of the IgG subclass distribution of antibodies can be informative in identifying an immunological deficiency, evaluating the production of host protective antibodies, and assessing pathophysiology. Determination of IgG subclass concentrations is essential in the diagnosis of immunodeficiencies. However, there is still uncertainty about the accuracy of measurements in relation to standards, monoclonal antibodies and assay types. For the paediatric population, a sensitive assay, such as an enzyme linked immunoabsorbent assay, is essential. A standardised definition of IgG subclass deficiency is yet to be accepted; however, values substantially below the 5th percentile for a normal healthy population of appropriate age measured by a defined assay system may be indicative of significant abnormality. There is emerging evidence that some subclass deficiencies are associated with increased susceptibility to infection. Such IgG subclass deficiencies may be amenable to treatment with intravenous gammaglobulin preparations, but further carefully designed and controlled studies are needed to ascertain treatment efficacy.     

Phenytoin-induced IgG2 and IgG4 deficiencies in a patient with epilepsy

A five-year-old girl with epilepsy and recurrent respiratory infections was investigated for serum IgG subclass concentrations. She was diagnosed as having a combined deficiency of IgG2 and IgG4 with a decreased serum concentration of IgA and IgG3 and was given replacement therapy with i.v. immunoglobulins. Since then, she has been free from respiratory infections. After phenytoin therapy was stopped, IgG subclass deficiency improved. This case describes the further action of phenytoin on the immune system, adding IgG subclass deficiency to the list.     

The prognostic significance of specific IgG antibodies in insect sting allergy

Specific IgG antibodies against bee venom and bee venom components were studied in the serum of 40 bee-sting allergic patients, 60 bee keepers, and 31 control subjects. The highest titres were observed in successfully hypothesized patients and in bee keepers. Subclass-typing in bee-sting allergic patients showed the highest antibody levels in subclass IgG 2, followed by IgG 3, IgG 4 and IgG 1. During hyposensitization, a rise in specific IgG antibodies in all subclasses and against bee venom and all its components was found. The allergic reaction to bee stings disappeared with the rise of specific IgG antibodies, as demonstrated by a bee-sting challenge. After 6 months of hyposensitization therapy, the specific IgG antibodies remained above, and the specific IgE antibodies fell below, the pretreatment levels.     

Serum immunogiobulin G subclasses and serum immunogiobulin A in healthy Norwegian children and adults

IgG subclass concentrations were determined by a capture ELISA antibody assay using monoclonal antibodies to IgG₁, IgG₂, IgG₃, and IgG₄. All the antibodies had been tested for specificity in an IUIS/WHO collaborative study, and this was confirmed by us by testing against purified myeloma proteins representing the 4 subclasses. The sera to be tested were diluted to obtain optimal sensitivity in the lower normal range for each subclass. With these serum dilutions, the lower limit of reading was 1. 2 g/l for IgG₁, 0. 25 g/l for IgG₂, 0.04 g/l for IgG₃ and for IgG₄. Age specific reference limits of the IgG subclass concentrations were determined in serum samples from 138 healthy infants and children under 14 years of age and 66 adults. The reference limits for each age group were determined by calculating the mean ± 2 SD of the logarithms to the values and then taking the antilog of the results. IgA was determined by a turbidimetric method with a reading limit of 0. 1 g/l, and the reference limits were calculated from serum samples from the 138 children under 14 years of age and from 31 healthy adults. The age specific reference limits of the IgG subclasses and IgA are given. Several infants and children had IgG₄ levels below the lower reading limit. To determine lower reference limits of IgG₄ below the age of 7 years was therefore of little clinical significance.     

IgG subclasses and their clinical significance

IgG are the most common isotype of Ig and include four subclasses which differ from one another in the following ways: their initial amino acid sequence, their physical and chemical properties and the different serum concentrations reached with age. Every subclass has a specific biological function: the response to proteic antigens is prevalently mediated by IgG1 and IgG3, while IgG2 mediates the response to polysaccharide antigens. It is still unclear whether IgG4 are protective or sensitising antibodies; IgG1 and IgG3 also have a major ability to bind to the cells that mediate the immune response, while only IgG4 activate the complement using an alternative route. Although low levels of IgG subclasses may be temporary, deficiencies are often associated with various diseases: 1) recidivating bacterial infections involving the respiratory and digestive tracts, primarily sustained by capsulated or pyogenic microorganisms; 2) IgA deficiency; 3) absence of immune response following vaccination; 4) allergic or autoimmune diseases; 5) diseases of the CNS. IgG subclass deficiencies must therefore be looked for every time these diseases are diagnosed, also because subjects may benefit from gammaglobulin replacement therapy.     

IgG Subclass Concentrations in Preterm Neonates

Serum IgG subclass concentrations were measured in 158 sera from preterm, appropriate for gestational age, infants born between 27 and 37 weeks of gestation, pregnancy, delivery and neonatal period being uncomplicated in all cases. At birth the IgG subclass concentrations were inversely correlated to the degree of prematurity. The IgG subclass concentrations decreased mainly proportionately during the neonatal period. The most immature infants born before the 30th week of gestation had critically low concentrations of all IgG subclasses. All immature infants, already in the first week after birth, showed capacity for IgGl and IgG3 synthesis.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency (often occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumococcus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

IgG subclass deficiencies in children: Facts and fiction

The chance to analyse the four IgG subclasses arose with the publication of Terry and Fahey¹. Since then, a lot of new information on the role of subclasses and their deficiency states in humans has been obtained. This review tries to analyse critically our current knowledge of subclass deficiencies in children.     

Clinico-immunologic aspects of IgG subclass deficiency

Serum IgG contains 4 subclasses, IgG1 (60-66%), IgG2 (20-30%), IgG3 (less than or equal to 5%) and IgG4. Individual subclasses vary with respect to their physicochemical and biological properties. IgG subclass concentrations in serum are age dependent. IgG1 and IgG3 reach near to adult levels around the age of 3, IgG2 and IgG4 after the age of 6. Antibodies of certain specificities generally belong to a certain isotype (subclass) due to the isotype restriction. Patients with subclass deficiencies often suffer from recurrent infections. Those with IgG2 deficiency coften occurring with IgA and IgG4 deficiency) develop recurrent infection of the upper and lower respiratory tract often caused by pyogenic microorganisms (Haemophilus, Pneumo-(occus). Since early initiation of IVIG substitution therapy has a beneficial effect on long term prognosis the importance of early diagnosis is apparent.     

Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma

It was the aim of this study to investigate possible dysfunctions of the humoral immune system in asthmatic children with frequent respiratory infections. Forty‐one severe asthmatics (7–15 years of age), classified according to the Second Brazilian Consensus in Asthma (1998), were divided into two groups: group I (n = 12) had recurrent respiratory infections; and group II (n = 29) were without recurrent respiratory infections. Immunoglobulin (Ig)G, IgA and IgM levels (nephelometry), and IgE (radioimmunoassay) and IgG subclasses (enzyme‐linked immunosorbent assay), were evaluated using standard methods. Asthmatics with recurrent infections presented with worse clinical evolution, an increased number of hospital admissions, and a higher need of medication than the children without recurrent infections. There were no significant differences between the mean values of IgG, IgA or IgM levels, or IgE or IgG subclasses, in patients of both groups. A complete IgA deficiency was detected in two patients of group I (one was associated with IgG subclass deficiency). Deficiency of one or more IgG subclasses was verified in eight of 12 (66%) children from group I and in 16/29 (55%) from group II. The following deficiencies were found in both groups: IgG₃ (10/41), IgG₄ (three of 41), IgG₂ (two of 41), IgG₁ (one of 41), IgG₃‐IgG₄ (four of 41), IgG₁‐IgG₃ (two of 41), and IgG₁‐IgG₃‐IgG₄ (one of 41). There were a higher proportion of children with low IgG₄ levels in group I than in group II (p = 0.01). To conclude, IgA and IgG subclass deficiencies were detected in both severely asthmatic groups, with a predominance of IgG₃ subclass deficiency. However, low IgG subclass levels appear not to be a suitable predictor of the development of infections in asthmatic children.     

The IgG subclass level in children and adolescents with malignant diseases]

Children with malignant disease have an increased risk for bacterial infections. We investigated a possible correlation between septic episodes and decreased IgG subclass levels in 63 patients. At diagnosis 13 of 50 children showed decreased IgG subclass levels: 10x IgG4, 2x IgG1, and 1x IgG3 + IgG4 were reduced. Bone marrow infiltration by tumor cells did not increase the frequency of subclass reductions (4/25 with, 9/25 without bone marrow infiltration). The time course of subclass levels was followed during 37 febrile episodes (mainly fever of unknown origin, septicemia, pneumonia) of 23 children under cytostatic therapy. 6 patients showed transient low IgG subclasses: 2x IgG4, 1x IgG1, 1x IgG3, 1x IgG2 + IgG4, and 1x IgG1 + IgG3 + IgG4. Children with decreased IgG subclass levels appeared to occur more independently of leucopenia. In general, febrile episodes in children with subclass decreases did not last a longer period and did not occur more frequently than in children without IgG subclass deficiencies. In conclusion, the determination of IgG subclasses in cancer children at diagnosis or during chemotherapy did not add substantial information of prognostic or therapeutic relevance.