Clinical manifestations in selective IgA deficiency in childhood. A follow-up report.

Clinical manifestations in 40 children with selective IgA deficiency were studied during a follow-up period of 2-10 years. The patients were divided into two groups: group I consisted of 25 children with "sporadic" IgA deficiency and group II of 15 children with "familial" IgA deficiency. Respiratory tract infections including otitis media were frequent in both groups. Concomitant IgG2-IgG4 deficiency was found in two patients in group I. Longitudinal serum IgG levels were elevated significantly in both groups. Atopic complaints were observed in 10 children of the "sporadic" group, but only in two of the "familial" group. However, elevated serum IgE levels were more often found in group II. Two children of group I were mentally retarded and chromosomal examination showed abnormalities in both. Anti-IgA antibodies were detected in one child in group I and three children in group II. These three patients had an IgA deficient mother with class-specific anti-IgA antibodies. Concomitant IgG4-IgE deficiency was found in all four.

Familial selective IgA deficiency with circulating anti-IgA antibodies: a distinct group of patients?

Two families were investigated in which the mothers had selective IgA deficiency and circulating class-specific anti-IgA antibodies. Both gave birth to two children who were found to be IgA deficient. Three of these children developed anti-IgA antibodies before puberty. In vitro immunoglobulin production studies performed in the children of both families revealed an IgA B cell defect combined with IgA-specific excessive T suppressor function in all four. The mechanisms by which transplacental passage of maternal anti-IgA antibodies could have interfered with the developing IgA system in the offspring are discussed.

Screening for microalbuminuria in patients with diabetes mellitus: frozen storage of urine samples decreases their albumin content.

The influence of storage on urinary albumin concentration was prospectively studied with use of overnight urine specimens (Albustix negative) from 73 diabetic patients. From each urine sample four aliquots were taken. One was stored at 4 degrees C and assayed within two weeks, the other three were stored at -20 degrees C and assayed within two weeks and after two and six months. Albumin concentration was measured with laser immunonephelometry. The detection limit, 1 mg/L, suffices for the screening of diabetic patients for microalbuminuria. After storage for two and six months at -20 degrees C, significantly lower albumin concentrations were found. The difference was mainly caused by lower concentrations found in urine samples in which a precipitate had formed, which was the case in 22 and 25 samples, respectively. Thus, freezing of urine samples for determination of low concentrations of albumin may yield falsely low results. Urine samples are best stored at 4 degrees C and assayed within two weeks.

[The significance of determining humoral defense factors: Ig isotypes, specific antibodies and complement]. / De betekenis van de bepaling van humorale factoren van de afweer: Ig-isotypen, specifieke antistoffen en complement.

The diagnosis of an immunodeficiency is made after detailed clinical and laboratory investigations. To guide these investigations the Dutch Working Group on Immunodeficiencies had made a protocol for evaluating the functioning of the immune system of patients. The protocol is based on the report 'Immunodeficiency' from a WHO scientific group. This paper discusses the value of laboratory investigations on the following aspects of the immune system: immunoglobulins and their subclasses, primary and secondary antibody responses in vivo, and the complement system. The evaluation of these components of the defense system can firmly establish possibly occurring severe immunodeficiency states. Some cases of chronic and/or recurrent infections, however, remain enigmas that have to be resolved by future investigations on the interactions of infectious agents with the immune system.

[Immunodeficiency and chromosome instability]. / Immunodeficiëntie en chromosoominstabiliteit.

In this paper, a survey is given of the immunological disturbances in some chromosome instability disorders (e.g. Bloom syndrome, ataxia teleangiectasia and Nijmegen Breakage syndrome). Further, the clinical symptoms and the diagnostic approach will be discussed.

Prednisolone can increase glomerular permeability to proteins in nephrotic syndrome.

In patients with a nephrotic syndrome administration of prednisolone causes an increase of proteinuria. To elucidate the mechanism of this effect we have studied the acute proteinuric effect of prednisolone, 125 to 150 mg intravenously, in nine patients (7 M, 2F) with a nephrotic syndrome. Mean age (+/- SD) of the patients was 53 +/- 6 years, mean endogenous creatinine clearance 104 +/- 30 ml/min, and mean proteinuria 7.7 +/- 3.0 g/24 hr. After administration of prednisolone, urinary total protein excretion rose in all patients from a mean (+/- SEM) of 4.89 +/- 0.59 mg/min before to 9.09 +/- 0.99 mg/min at five hours after administration (P less than 0.01). Glomerular filtration rate (inulin clearance), effective renal plasma flow (PAH clearance), and filtration fraction did not change significantly. The increases of urinary excretion of albumin (median %: +92%), IgG (median %: +88%), and transferrin (median %: +76%) were comparable and correlated significantly. Urinary excretion of beta 2-microglobulin did not change significantly however. We conclude that intravenous administration of prednisolone to patients with a nephrotic syndrome causes an increase in urinary protein excretion rate which cannot be explained by changes in renal hemodynamics or tubular protein reabsorption, and which therefore must be the result of a change in glomerular permselectivity characteristics.

Four methods compared for measuring des-carboxy-prothrombin (PIVKA-II).

PIVKA-II (Protein Induced by Vitamin K Absence) is abnormal des-carboxylated prothrombin, which is present in vitamin K deficiency or in patients using warfarin. With a sensitive method for PIVKA-II, biochemical vitamin K deficiency can be established before clinical symptoms occur. We give an overview of methods used to detect PIVKA-II, and four selected methods are inter-compared: (a) measuring total factor II including PIVKA-II by using Echis carinatus snake venom as an activator of prothrombin; (b) measuring PIVKA-II by using snake venom as an activator of factor II after adsorption of functional factor II onto barium sulfate; (c) electrophoresis-immunofixation method; and (d) enzyme immunoassay. We found d to be the most sensitive and reliable method for PIVKA-II.

Enrichment of subgingival microflora on human serum leading to accumulation of Bacteroides species, Peptostreptococci and Fusobacteria.

This study was undertaken to identify ecological factors that favour opportunistic pathogenic species in the subgingival microflora. In a first approach, human serum as a substitute for gingival exudate, was used for batch-wise enrichment of subgingival plaque. The microflora resulting after 5-6 enrichment steps consisted of black-pigmented and non-black-pigmented Bacteroides species, Peptostreptococcus micros and Fusobacterium nucleatum as the main organisms. It is noted that the same group of species was found to be enriched independent upon the origin of the subgingival plaque sample. It was suggested that these organisms are favoured by the increased flow of gingival exudate during inflammation. The consortium of organisms was capable of selective degradation of serum (glyco-)proteins. Four different types of degradation occurred. After a prolonged period of growth complete degradation of immunoglobulins, haptoglobin, transferrin and complement C3c was observed. Partial degradation of immunoglobulins, haptoglobin, transferrin, albumin, alpha 1-antitrypsin and complement C3c and C4 was generally observed after 48 h of growth. Besides, immunoglobulin protease activity yielding Fc and Fab fragments was found. The consortium was also capable of consuming carbohydrate side-chains as indicated by an altered electrophoretic mobility of the serum glycoproteins.

Nephelometry of the kappa/lambda light-chain ratio in serum of normal and diseased children.

We determined, immunonephelometrically, the ratio between the two types of light chains of immunoglobulins, kappa and lambda, in serum of 94 children, ages 0.4 to 14 years, with no manifest immunological disorders. Children with an abnormal protein pattern by immunoelectrophoresis show other values for this ratio than do children in this reference group. We also determined the ratios for children with IgA deficiency (I), juvenile rheumatic arthritis (II), and acute lymphoblastic leukemia (III). Children with I show the same kappa/lambda ratios as for the children in the reference group. Children with II also show the same mean kappa/lambda ratios, but a significantly wider range of ratios. In children with III, the ratio during chemotherapy is slightly depressed, significantly lower than after cessation of therapy. All groups--healthy children and patients--show an increase in kappa-chain-bearing immunoglobulins with age, but the concentration of lambda-chain-bearing immunoglobulins remains relatively constant.

Posttraumatic complications and inflammatory mediators.

In a series of 71 patients with trauma, we measured weekly the blood levels of a number of complement proteins and activation products. We also measured the following: leukocytes, platelets, granulocyte enzyme elastase, alpha 1-antitrypsin, total protein, albumin, haptoglobin, and fibronectin. The intensity of complement activation and the blood levels of elastase correlated with the following factors: injury severity (especially the severity of limb injury), development of adult respiratory distress syndrome, development and severity of multiple organ failure, and probability of a fatal outcome. The plasma elastase level seemed to be the best predictor of adult respiratory distress syndrome and the best correlate of injury severity and multiple organ failure severity. Our findings support the hypothesis that posttraumatic activation of the complement system leads to activation of granulocytes, followed by microvascular injury and finally by organ failure.

Biochemical vitamin K deficiency in early infancy: diagnostic limitation of conventional coagulation tests.

Thrombotest, factor II and factor X determinations were performed in two groups of children, one receiving a low vitamin K diet (breast-feeding) and one receiving a high vitamin K regimen (formula-feeding). No infant received vitamin K at birth. Thrombotest values were found to be lower at day 30, 60 and 90 after birth, and factor II levels unexpectedly higher at day 30 and 60 in breast-feeding group compared to the formula-feeding group. No difference in factor X levels could be detected. Compared to the direct measurement of PIVKA II by a highly sensitive immunological method, these coagulation tests are inadequate to detect biochemical vitamin K deficiency.

Immunological investigations in individuals with selective IgA deficiency.

Concentrations of IgG2, IgG4 and IgE were low in 16, 24 and 20% of 25 persons with selective IgA deficiency. Fifty-two per cent had IgD concentrations below 5 iu/ml. Trends for association between any of these parameters and the presence of clinical symptoms were not significant. All patients, except one, had normal amounts of Ig-bearing lymphocytes in the blood. IgG1 antibodies against casein were increased in titre and frequency, whereas IgG4 antibodies were normal. Similar results were found in other sera from persons with selective IgA deficiency.

Platelet aggregating factor in the epidemic form of hemolytic-uremic syndrome in childhood.

Plasma from six out of eleven children with the epidemic forms of hemolytic-uremic syndrome caused the aggregation of homologous platelets as has been described in thrombotic thrombocytopenic purpura. IgG purified from normal adults inhibited the platelet aggregation induced by plasma collected from three children during the acute phase of the disease. This inhibition by IgG may contribute to the reported successful management by infusions of plasma or plasma exchanges.

Effects of angiotensin II blockade in the canine puppy under different salt-intake.

The objective of this study was to investigate the relationship between the high activity of the renin-angiotensin-aldosterone system (RAAS) and the control of blood pressure and aldosterone in the canine puppy. The effect of the angiotensin II analog saralasin on arterial pressure (MAP), plasma renin activity (PRA), plasma renin concentration (PRC), and aldosterone (PA) was studied in unanesthetized normal, salt-loaded and salt-depleted puppies aged 9 to 30 days. Salt-loading was performed by daily intraperitoneal administration of 10 mEq sodium/kg body weight for 5 days and salt-depletion by furosemide injections. Saralasin infusion, 6 micrograms/kg/min, during 60 min significantly decreased MAP and increased PRC not only in salt-depleted puppies, as has been observed in adult salt-depleted dogs, but also in normal puppies (mean fall, 6.6 mm Hg). Although any developmental changes in the RAAS and MAP and in their relationship could not be ascertained, the fall in MAP during saralasin in normal puppies was significantly correlated to presaralasin renin values (r = 0.76, P less than 0.01, N = 11). PA did not change in both groups of puppies. In salt-loaded puppies saralasin caused no change of MAP, PRC, and PA. We conclude that the high renin levels at young age contribute to the basal arterial pressure in puppies.

The renin-angiotensin-aldosterone system in infancy and childhood in basal conditions and after stimulation.

Plasma renin activity (PRA), aldosterone (PA), sodium and potassium concentration were measured in 107 healthy infants and children under basal conditions of normal diet and recumbency. Urinary aldosterone (UAldo), sodium and potassium were also measured (n = 51). A significant (P less than 0.001) age-related decrease in PRA (r = -0.67), PA (r = -0.67), UAldo (r = -0.56) was observed, with a striking scatter of values especially in infancy. The reninangiotensin-aldosterone system (RAAS) was also studied after stimulation by standardised sodium restriction during 4 days, followed by acute postural change (n = 40). After salt restriction a rise of PRA and UAldo was noted, but a rise in PA could not be demonstrated in children aged 0-6 months. The influence of postural change on the RAAS seems more important in older children. The reported values not only in basal but also in stimulated conditions allow study of the RAAS in diseases such as salt loss and hypertension.

The basal levels of active and inactive plasma renin concentration in infancy and childhood.

Basal plasma renin activity, active and inactive plasma renin concentration were measured in 89 healthy recumbent children aged between 1 week and 16 years. A significant (P less than 0.001) age-related decrease for active (r = -0.60), inactive (r = -0.59) and total renin concentration (r = -0.66) was observed. After correction for the influence of age, active renin concentration correlated with plasma renin activity (r = 0.81), but not with inactive renin concentration (r = 0.18). The proportions of active and inactive renin were not related to age, and the overall percentage of inactive renin was 79%.

Antibody responses in vivo in chromosome instability syndromes with immunodeficiency.

The primary IgG, IgM and IgA antibody responses to Helix pommatia haemocyanin (HPH) were defective in patients with ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS). The results in patients with Bloom's syndrome (BS) were heterogeneous, but all showed abnormal kinetics of the IgG response. The secondary response to diphtheria, tetanus and polio vaccine was normal in patients with AT and BS, but disturbed in the patients with NBS. The abnormalities of antibody response of AT and NBS are similar, although more profound in NBS; BS is different.

[Effect of age and sex on the enzyme activities of serum aspartate and alanine aminotransferases]. / Invloed van leeftijd en geslacht op de enzymactiviteiten van aspartaat- en alanine-aminotransferase in serum.

Reference values of ASAT and ALAT are calculated from all the results over a period of two years. For each test age- and sex-related variations were assessed and reference values were estimated for six different age groups. The activities of both enzymes are sex independent. The activity of ASAT decreased with increasing age whereas the activity of ALAT did not show different reference values between the age categories.

[Immunologic and cytogenetic aspects of ataxia telangiectasia]. / Immunologische en cytogenetische aspecten van ataxia telangiectasia.

Immunological and cytogenetic studies were performed in 6 patients with ataxia telangiectasia (AT). Immunological disturbances were found in these patients: immunoglobulin deficiencies (IgA, IgE, IgG2 and IgG4), decreased cellular immunity and a defect in the synthesis of specific antibodies. Cytogenetic studies revealed chromosome 7 and/or 14 abnormalities in all patients. X-irradiation of AT cells induced an excessive increase in chromosome and chromatid breaks. The DNA synthesis inhibition after X rays was less in AT patients compared to controls. The possibilities of early diagnosis and the eventual relationship between immunological and cytogenetic findings are discussed.