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.     

Humoral immunity in children with proven bronchiectasis, bronchial deformations and chronic bronchitis

In 70 children with defined chronic chest disease, immunoglobulins, IgG subclass levels and antibody concentrations specific for Haemophilus influenzae b (Hib), and pneumococcal antigen, were related to disease severity. Bronchological examinations revealed 30 children with chronic bronchitis, 21 with bronchial deformations and 19 with bronchiectasis. Of the 70 children 12 (17.1%) showed an underlying immunodeficiency. The commonest finding was an IgG subclass deficiency, 7 were IgG₂ and 1 IgG₃ deficient, followed by IgA deficiency in 3 patients. All patients had normal IgG and IgM levels except one who had immunodeficiency with elevated IgM. Pneumococcal antibody levels were found to increase between patient groups in the order healthy children < chronic bronchitis < bronchiectasis < bronchial deformations (p < 0.01), but this was not the case for Hib antibodies. We found no selective deficiency of pneumococcal and Hib antibodies in our patients. Pathogens were detected in bronchial cultures from 10% of patients with chronic bronchitis, 33% of those with bronchial deformations and in 63% with bronchiectasis. This increase (p < 0.01) reflects a more severe inflammation of the respiratory tract in such patients. However, immunodeficiencies were equally distributed between patient groups. We conclude that only a subgroup of children with chronic chest disease have an underlying immunodefiency, but most patients (83%) do synthesize normal or even high antibodies in the presence of a bacterial load.     

IgG Subclass Imbalance in Children with Acute Lymphoblastic Leukemia Receiving Maintenance Chemotherapy

Serum levels of IgG subclasses were measured in 18 children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy and in 36 age-matched controls in order to attempt to analyse the effects of chemotherapy. The IgG subclasses were measured by enzyme linked immunosorbent assay. Serum IgG₁, IgG₂ and IgG₄ levels in the patients were significantly (p<0.01, p<0.005, p<0.005) lower than in the controls, but serum IgG₃ levels in patients were as high as in controls. Suppression on IgG₂ and IgG₄ were more profound than IgG₁. In six children, the levels of the IgG subclasses were measured at diagnosis, during maintenance chemotherapy and one year after cessation of chemotherapy. The levels of the four IgG subclasses at diagnosis and after cessation of chemotherapy were as high as those in control children except for the IgG₄ levels in the postchemotherapy group. IgG₂ and IgG₄ may be more susceptible to suppression by chemotherapy than IgG₁ and IgG₃ may not be suppressed by chemotherapy.     

Reduced levels of IgG subclasses and IgA in young children with asthma

Serum immunoglobulins including IgG subclasses were measured in 73 unselected children with asthma. The results showed that 22 (30%) had partial IgA and/or IgG₄ subclass deficiency. Clinical assessment showed that 21 children were infection-prone, and 52 were not. Further analysis showed that infection-prone children were significantly different from non-infection-prone children with regard to familial history of allergy (29% vs 60%, p = 0.015), elevated IgE (62% vs 33%, p = 0.021), IgA deficiency (38% vs 15%, p = 0.38) and IgG subclass deficiency (24% vs 4%, p = 0.018). These results suggest that there may be subgroups of children with asthma who are also immunodeficient.     

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.     

Milk and ovalbumin-specific IgG4 in childhood atopic eczema: serum levels in relation to dietary changes

Serum levels of cow milk-specific IgG₄ (IgG₄-milk) and ovalbumin-specific IgG₄ (IgG₄-ova) were found to be raised in a group of children with atopic eczema. Patients with the highest levels had IgE-mediated hypersensitivity to some foods but no correlation with IgG₄ results. Initial IgG₄ levels did not predict whether the eczema would improve after a diet eliminating cow milk, egg and some other foods. Changes in IgG₄-milk during double-blind milk challenges did not correlate with clinical changes in patient's eczema as measured by skin assessment. There seems to be no clinical value in measuring IgG₄ antibodies to milk and ovalbumin in children with atopic eczema, the high titres reflecting antigen response only.     

Is Oxygen Supply the Only Regulator of Erythropoietin Levels?Serum Immunoreactive Erythropoietin during the First 4 Months of Life in Term Infants with Different Levels of Arterial Oxygenation

ABSTRACT. Serum immunoreactive erythropoietin (siEp) levels were measured in 35 full-term infants aged 0–13 weeks, 31 of whom had congenital heart disease. The infants displayed a wide range in arterial oxygen tension (Pa_o2) and oxygen saturation (Sa_o2). During the first days of life siEp varied widely with a range from less than 3 to more than 10000 mIU/ml. The wide variation is consistent with findings in cord blood at term. The siEp levels did not correlate significantly with haemoglobin, haematocrit, Pa_o2, Sa_o2, or arterial oxygen content in the total sample, nor when the cohort was split up into different age groups. Cyanotic infants aged 2–13 weeks had significantly higher siEp concentrations than normal adults ( p <0.001) and than children with cyanotic congenital heart disease, aged 4 months-10 years ( p <0.001). The raised siEp levels in cyanotic children aged 2–13 weeks found in this study and the normal levels found in their older counterparts (4 months-10 years) (reported elsewhere) are consistent with the pattern observed in man and animals exposed to prolonged hypobaric hypoxia, in which after an initial rise in erythropoietin concentrations the levels fall to normal while increased erythropoiesis is sustained.     

Energy and nutrient intakes in congenital heart disease

Children with congenital heart disease may have significant growth retardation, which in part may be caused by insufficient dietary intake. Data on energy and nutrient intake were collected using a 14-day dietary record by weighing, in 22 children with congenital heart disease (mean age 39 months, range 12–126 months), prior to corrective operation. When viewed in relation to actual weight, energy intake averaged 88% (SD 17%) of that recommended by the FAO/WHO/UNU. Energy intakes and weight SD scores were significantly correlated ( r = 0.55, p < 0.01). Protein intake was generally high, and even sufficient to allow catch-up growth. The majority of the children did not meet the recommendations for iron, zinc, calcium, or vitamins D, E, C, B₁ or B₆. Parents should be advised to give their children vitamin/mineral supplements, and to supply extra energy to children with failure to thrive.     

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.     

Treatment of children with congenital heart disease and growth retardation with recombinant human growth hormone

Seven prepubertal short children with congenital heart disease were treated with recombinant human growth hormone (GH). Although complete surgical correction was performed for their heart disease at least 2 years before the start of GH therapy, improvement in growth was less than expected in these children. They received 0.5 IU kg⁻¹ week⁻¹ of GH daily for 2 years or more. The growth rate increased from a mean of 4.3 cm year⁻¹ before treatment to a mean of 7.8 cm year⁻¹ in the first year and to a mean of 6.3 cm year⁻¹ in the second year of treatment. Their mean standardized height improved from −3.41 ± 0.78 to −2.54 ± 0.62 after 2 years. The mean height age difference minus the bone age difference became positive in these children. We conclude that recombinant GH increases the growth rate in children with congenital heart disease and prepubertal growth retardation.     

T AND B LYMPHOCYTE SUBPOPULATIONS AND LEUKOCYTE TERMINAL DEOXYNUCLEOTIDYL-TRANSFERASE IN ENERGY-PROTEIN UNDERNUTRITION

Abstract. Children with energy-protein undernutrition showed a reduction in the number of circulating T lymphocytes identified on the basis of their ability to form rosettes with sheep red blood cells. T cells with a receptor for IgM (T_μ) were decreased whereas T cells with a receptor for IgG (T_γ) were increased. Surface immunoglobulin bearing B cells were comparable in well nourished and malnourished subjects but the proportion of B_α was increased in the latter. "Null" cells without the conventional markers of T or B cells were proportionately increased. Leukocyte terminal deoxynucleotidyltransferase activity was elevated in the majority of undernourished children and correlated with the proportion of "null" cells. The significance of these observations is discussed and it is suggested that "null" cells represent immature undifferentiated T lymphocytes.     

LYMPHOCYTE SUBPOPULATIONS IN PATIENTS WITH VARIOUS IMMUNODEFICIENCIES

Abstract. Gmelig-Meyling, F., Dollekamp, I., Zegers, B. J. M., Ballieux, R. E. and Stoop, J. W. (University Children's Hospital "Het Wilhelmina Kinderziekenhuis" and Department of Clinical Immunology, University Hospital, Utrecht, The Netherlands). Lymphocyte subpopulations in patients with various immunodefciencies. Acta Paediatr Scand, 69: 193, 1980.—We have studied patients with various immunodefciencies for the occurrence of blood lymphocytes bearing six different surface markers: the affinity to sheep erythrocytes(E _S )to identify T cells, the presence of surface-bound immunoglobulins (sIg) to distinguish B cells, the affinity to mouse erythrocytes (E _m ) as a second B cell marker, and the receptors for the Fc part of IgM (IgM-FcR), the Fc part of IgG (IgG-FcR) and for complement (CR). IgG-FcR bearing lymphocytes were present in normal proportions and the same was found for CR-positive lymphocytes. None of the patients with congenital agammaglobulinaemia had sIg-bearing or E _m -binding B lymphocytes. Four patients with ataxia teleangiectasia had low B cells and 3 out of 4 also had low proportions of IgM-FcR-bearing (T) cells. A child with partial DiGeorge syndrome did not have a grossly abnormal marker pattern although there appeared to be a shift in the T/B cell ratio in favour of the B cells. In a patient with selective cellular immunodeficiency associated with a purine nucleoside phosphorylase deficiency, who was followed during reconstitution therapy with plasma and red cells, a positive change in the marker pattern was seen. Similar observations were made in a child with combined immunodeficiency during treatment. The findings are being discussed in the light of the current knowledge of the functions and ontogeny of lymphocyte subsets.     

Pharmacologically Active Levels of PGE-, in Neonates with Congenital Heart Disease

ABSTRACT. In general, prostanoids act as local mediators, not as circulating hormones. A specific exception to this rule is the infusion of prostaglandin E₁ in patients with ductus arteriosus-depend-ent pulmonary or systemic blood flow associated with congenital heart disease. We therefore measured prostaglandin E, plasma levels by gas chromatography-mass spectrometry during effective infusion of prostaglandin E₁ in 10 neonates. Prostaglandin E₁ plasma levels ranged from 22 to 530 (median 56) pg/ml in these patients. Since prostaglandin E₁ is not synthesized endogenously to any significant extent, these plasma concentrations constitute genuine circulating levels not confounded by the common problem of e vivo artifacts. If endogenous prostanoids (e.g. prostaglandin E₂) are suspected as circulating mediators, plasma levels detected by reliable methods ought to be in the same range as prostaglandin E₁ plasma levels in the present investigation.     

The Value of the Sinusoidal tcPO2 Pattern in the Evaluation and Management of Cyanotic Congenital Heart Disease with Ductus Dependent Lesions

A characteristic sinusoidal tcPO₂ pattern was observed in 17(27%) of 62 patients with congenital heart disease manifested by cyanosis or heart failure during the neonatal period. All of these 17 patients were definitively diagnosed by cardiac catheterization, as having 8 PPA; 3 ToF; 2 TCA+VSD+PA; 2 asplenia with PA; 1 TGA+VSD+PS; and 1 TA (no TCA type). The transcutaneous oxygen pressure pattern of these patients showed a sinusoidal change with a cycle length of 6–20 min with the maximum pressure not exceeding 50 torr and the minimum pressure occasionally close to 0 torr. This sinusoidal tcPO₂ pattern was associated with various types of ductus-dependent congenital heart diseases and hence may be of diagnostic value. Transcutaneous oxygen pressure monitoring is also useful in evaluating the ductal response to PG. Other possible mechanisms underlying this phenomenon including biological oscillation should be considered.     

The association between ketoacidosis and 25(OH)-vitamin D levels at presentation in children with type 1 diabetes mellitus

Background:  There is considerable evidence supporting the role of vitamin D deficiency in the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D deficiency is also associated with impairment of insulin synthesis and secretion. There have been no formal studies looking at the relationship between 25(OH)-vitamin D₃ and the severity of diabetic ketoacidosis (DKA) in children at presentation with T1DM.
Objective:  To determine the relationship between measured 25(OH)-vitamin D₃ levels and the degree of acidosis in children at diagnosis with T1DM.
Subjects:  Children presenting with new-onset T1DM at a tertiary children's hospital.
Methods:  25(OH)-vitamin D₃ and bicarbonate levels were measured in children at presentation with newly diagnosed T1DM. Those with suboptimal 25(OH)-vitamin D₃ levels (<50 nmol/L) had repeat measurements performed without interim vitamin D supplementation.
Results:  Fourteen of the 64 children had low 25(OH)-vitamin D₃ levels at presentation, and 12 of these had low bicarbonate levels (<18 mmol/L) (p = 0.001). Bicarbonate explained 20% of the variation in vitamin D level at presentation (partial r² = 0.20, p < 0.001) and ethnic background a further 10% (partial r² = 0.10, p = 0.002). The levels of 25(OH)-vitamin D₃ increased in 10 of the 11 children with resolution of the acidosis.
Conclusions:  Acid–base status should be considered when interpreting 25(OH)-vitamin D₃ levels in patients with recently diagnosed T1DM. Acidosis may alter vitamin D metabolism, or alternatively, low vitamin D may contribute to a child's risk of presenting with DKA.     

Immunological evaluation and clinical aspects of children with congenital cytomegalovirus infection

ABSTRACT  To determine the ability of immunological response to human cytomegalovirus (CMV), the flow cytometric assay was evaluated as a tool for real-time monitoring of specific cellular immunity in children with congenital CMV infection. Longitudinal cohort study of 2 children with asymptomatic and 2 with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. Frequencies of CMV-specific CD4⁺ T cell in these children were detected by intracellular cytokines (ICC), interferon (IFN)-γ and tumor necrosis factor (TNF)-α, staining.
Findings detected by CT and MRI were the most sensitive predictor for neurodevelopmental prognosis. Frequencies of CMV-specific CD4⁺ T cells detected by ICC, both IFN-γ and TNF-α, were higher in 2 children with symptomatic congenital CMV infection than those in 2 children with asymptomatic congenital infection. Frequencies of CMV-specific CD4+ T cells in 2 children with symptomatic congenital infection were significantly higher than those in 6 healthy children of 1 to 5-years of age with serum anti-CMV IgG antibody without serum anti-CMV IgM antibody and viral excretion in to urine ( p < 0.01). The ICC assay reflects immunological activity against CMV infection in children with asymptomatic or symptomatic congenial infection. Categorizing findings obtained by the ICC assay may helps to determine the prognosis of children with congenital CMV infection.     

Usefulness of antiendomysial antibodies as a serological marker in coeliac children

The new diagnostic criteria of coeliac disease (CD) give more importance to serological markers. Immunoglobulin A antiendomysial antibodies (IgA-EmA) were determined in 138 sera from 79 coeliac children and the antibody levels compared to IgG and IgA antigliadin antibodies (IgG-AGA, IgA-AGA) in the sera. The assessment was also carried out in 29 children with other gastrointestinal diseases, 29 with non-gastrointestinal diseases and 35 healthy children. The IgA-EmA had a 91.4% specificity and a 88.4% sensitivity for active CD. The corresponding figures were 89.8% and 64.4% for IgA-AGA and 73.7% and 86.2% for IgG-AGA, respectively. The results of IgA-EmA determinations were concordant with the intestinal biopsy findings in 90% of cases, versus 80% for IgA-AGA and 83% for IgG-AGA. In most of the discordant cases the biopsy showed only minor changes, making the classification difficult. All patients with positive IgA₂-EmA also had positive IgA₁ EmA antibodies. IgA-EmA are an excellent serological marker of CD activity in children and they are useful to decrease the number of intestinal biopsies which are needed to confirm the diagnosis in coeliac patients.     

High and low dose initial thyroxine therapy for congenital hypothyroidism

Objective : To assess factors influencing thyroxine (T₄ levels 1 month after initiating replacement therapy for congenital primary hypothyroidism.
Methodology : A retrospective review of 41 children with congenital hypothyroidism who received either high or low dose initial T₄ therapy. Thyroid scintiscan was performed, and T₄ levels determined before starting treatment and after 1 month.
Results : T₄ levels at 1 month were correlated ( r ²=0.38, P <0.001) with the pretreatment T₄ level ( r = 0.48), as well as with the T₄ dose ( r = 0.46). Suboptimal treated T₄ levels (<130nmol/L) were seen with greater frequency in infants with thyroid agenesis (7/11) rather than ectopia (7/28, P <0.03), despite receiving similar doses of thyroxine. Infants with suboptimal treated T₄ levels had lower pretreatment T₄ levels than those with optimal levels (21±7 vs 48±34nmol/L, P <0.02). Biochemical hyperthyroidism (T₄ >216nmol/L) occurred in six patients: four of six had ectopia.
Conclusions : These data suggest that infants with little residual thyroid function should receive higher initial T₄ doses than those with significant ectopia.     

Down syndrome and arterial ischemic stroke in childhood: A potential immunologic link with selective IgG4 subclass deficiency

We report four children with Down Syndrome (DS) without evidence of congenital heart disease who sustained cerebral infarction in the context of an infectious disease. In one child, stroke occurred in the context of acute infection with Mycoplasma pneumonia. In another child, stroke occurred in the context of Streptococcus oralis (viridans subgroup) infection. In two other children, stroke occurred in the context of a bibasilar pneumonia for which an etiologic agent was not found. All patients had evidence of selective IgG4 subclass deficiency. We followed 8 other children with down syndrome with infectious diseases, but without stroke and a control group of healthy children, and measured the value of IgG4 for each group. We found a statistical significant difference of levels of IgG4 subclass deficiency in the group of stroke, in comparison with the other two groups (P values <0.001). We, therefore, suggest an association between IgG4 subclass deficiency and stroke in DS patients. IgG4 subclass deficiency could conceivably play a role in the high frequency of para-infectious related stroke in this population.     

Leukotriene C4 in Children with Atopic Asthma I. Plasma Levels in Acute Asthma

The leukotrienes C₄, D₄ and E₄ are potent biologic mediators, and are thought to play an important role in obstructive airways disease such as asthma. In this study, plasma im-munoreactive LTC₄ (iLTC₄) levels in asthmatic children were measured using radio-immunoassay after Sep-pak extraction in order to determine whether LTC₄ is released in vivo during an asthmatic attack. In 10 non-atopic children, the mean ± SEM of plasma iLTC₄ level was 0.031 ± 0.013 pmol/ml. Significantly higher plasma iLTC₄ levels were recognized at all stages in asthmatic children, both in remission (p<0.01) and during an attack (p<0.01). PaO₂ levels during an attack were significantly lower in the high iLTC₄ group. In 15 asthmatic children, the plasma iLTC₄ levels during an attack (0.134 ± 0.017 pmol=ml) significantly decreased during recovery (0.078 ± 0.012 pmol/ml) (p<0.05). Plasma iLTC₄ levels correlated closely with lung function (p<0.01). The high iLTC₄ levels in plasma in asthmatic children suggest a role for LTC₄ in the pathophysiology of asthma.