Outcome of Henoch-Schoenlein nephritis with nephrotic-range proteinuria.

PATIENTS AND METHODS: All children with Henoch-Schoenlein glomerulonephritis (HSP-GN) and nephrotic-range proteinuria (> 40 mg/h/m2), treated at 5 university hospitals and in 1 central hospital in Finland during in 1990-1997, were analyzed retrospectively. The mean age of these 19 patients (8 girls, 11 boys) at the time of diagnosis was 9.9 years (range 4.6-15.1 years). A renal biopsy had been performed in all cases, giving findings according to the classification used in the International Study of Kidney Diseases in Children (ISKDC) of grade II (4 patients), grade III (10), grade IV (4) and grade V (1). Six patients underwent a second biopsy. RESULTS: The yearly incidence of nephrotic-range HSP-GN in Finland was 2 per 1 million children under 15 years of age. After a mean follow-up of 4.6 years (range 9 months-9.1 years), 3 patients (15.7%) had no signs of nephritis, 11 (57.9%) had proteinuria < 1 g/day or microscopic hematuria, 2 (10.5%) had proteinuria > 1 g/day, and 3 (15.7%) had developed ESRD or uremia. 47% of the patients needed medication for proteinuria at the time of the latest follow-up. The first kidney biopsy did not predict the outcome of HSP-GN, since all the patients with the poorest outcome had only ISKDC II-III findings in their first biopsy. CONCLUSION: According to our series, the morbidity in cases of HSP-GN with nephrotic-range proteinuria is high and a close clinical follow-up is needed. The treatment of HSP-GN patients should be based on the clinical presentation rather than on the biopsy findings.

T cells of the colonic mucosa in patients with infantile colitis.

BACKGROUND: Infantile colitis is a heterogeneous group of disorders, including enterocolitis complicating Hirschsprung disease, allergic colitis, inflammatory bowel disease, and Behçet syndrome. There are limited data concerning the immune responses induced by the inflammation of the intestine in young infants. METHODS: Twenty-four colonic biopsy specimens from 12 infantile colitis patients and 12 age-matched control patients were studied by immunohistologic methods. The authors compared the T cells, their subsets expressing the surface antigens CD8 and CD4, and T-cell receptors alphabeta and deltagamma, and densities of mononuclear and epithelial cells expressing human leukocyte antigen class II antigens. RESULTS: The density of CD3+ intraepithelial lymphocytes (IELs) in the large intestinal specimens was significantly higher (P = 0.036) in colitis patients than in the control group. The majority of the CD3+ IELs were CD8+-expressing cells, and only a minority were CD4+ cells in both groups. T-cell receptors alphabeta+ (P = 0.023) and deltagamma+ (P = 0.027) IELs were observed significantly more frequently in colitis patients than in the control group. In surface epithelium, delta non-disulphide-linked type T-cell receptor (deltaTCS1) IELs were found strikingly more frequently (P = 0.001) in the specimens taken from the colitis patients. Also, the density of the deltaTCS1+ cells in crypts of the large intestine was significantly higher in colitis patients than in the control patients (P = 0.047). CONCLUSIONS: A significant increase of CD3+ lymphocytes in the colonic epithelium of the patients with infantile colitis was noted. This increase involved both T-cell receptor alphabeta-positive and deltagamma-positive IELs. The finding of this study supports the proposal that intraluminal antigens, either microbial or food derived, are important in the pathogenesis of colitis in young infants.

Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature.

UNLABELLED: Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia. The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia. Although 25 patients have been reported with this disorder, the clinical course and phenotype of SIOD are not well characterized. This report summarizes the clinical findings, course and treatment of reported patients and includes 14 additional patients with SIOD. We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies. CONCLUSION: Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

B-cell development in lamina propria of the large intestine: influence of age and t-cell densities.

The development of B-cells and immunoglobulin-isotype and IgA subclass-positive cells in the lamina propria of the large intestine during infancy was investigated. Biopsy specimens from 36 infants, taken for diagnostic purposes, were available. All samples showed normal morphology. Monoclonal antibodies to CD22, IgA, IgA1, IgA2, IgM and IgG and a peroxidase method were used to demonstrate positive cells in the cryostat sections. Cell densities were counted from a known area. T-cells had been measured in a previous study using the same specimens. The density of CD22+ cells was already high in infants below the age of 1 month and increased little with age. Four specimens from infants below the age of 40 days lacked IgA-, IgA1- and IgA2-positive cells. The densities of these cells increased with age; the correlation coefficient between the age and the density of the cells was for IgA: R=0.47, p=0.04; for IgA1: R=0.57, p=0.001, and for IgA2: R=0.34, p=0.04. The densities of IgG- and IgM-positive cells remained unchanged with age. The negative correlation between density of IgG+cells and CD8+ cells in the lamina propria (R= -0.43, p=0.01) was significant. Strong local stimulation results in early accumulation of CD22+, IgM+ and IgG+ cells in the large intestine, but little change takes place after the first few days of life. The terminal differentiation to IgA-positive cells is slowest, and this population showed significant developmental change.

Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation.

The roles of enteric viruses and food antigens as possible triggers in human insulin-dependent diabetes mellitus and the evidence that mucosal-associated homing receptors are important in both human and experimental diabetes prompted us to undertake an immunohistochemical study of intestinal specimens from patients with IDDM. We studied jejunal morphology and immunohistochemistry in 26 patients with IDDM, 13 of whom had the HLA-DQB1*0201 gene and therefore a higher risk of coeliac disease. The findings were compared with those in specimens from age-matched controls. Villous structure and the density of the intraepithelial lymphocytes were normal in every biopsy specimen. The extent of positivity with anti-DR and -DP antibodies in the villous epithelium was significantly greater in the specimens from patients than in those from controls (P = 0.0002 in both comparisons). The crypts were also more positive: for DR P = 0.0001, and for DP P = 0.002. The densities of T cells, CD4+, CD8+, and T cell receptor alpha/beta+ and gamma/delta+ cells in the epithelium and lamina propria were similar in patients and controls, but the patients had significantly more alpha 4/beta 7 integrin+ cells in the lamina propria (P = 0.006). No difference was seen between HLA-DQB1*0201-positive and -negative patients. These findings reflect a stage of inflammation in the structurally normal intestines of patients with IDDM and suggest secretion of inflammatory Th1-type cytokines in the intestine.

Autoimmune enteropathy in Schimke immunoosseous dysplasia.

The clinical phenotype of Schimke immunoosseous dysplasia (SID) is characterized by growth retardation, renal failure, recurrent infections, cerebral infarcts, and skin pigmentation beginning in childhood. We report here on a 4-year-old male child who had all characteristic symptoms of SID, and, in addition, vomiting and prolonged diarrhea. The study results suggest that malabsorption, demonstrated as increased serum immunoglobulin A anti-gliadin antibody, steatorrhea and partial villous atrophy of the jejunal small bowel, is a previously unrecognized feature of SID.

T-cells and HLA-class II expression in the large intestine of infants in the early postnatal period.

BACKGROUND: There is only limited knowledge of the development of the immune responses of the gut in very young infants after exposure to bacterial and food antigens at birth. METHODS: In this study, 49 large intestinal biopsy specimens, which were judged to have normal morphology, were taken from 49 young infants. Eleven patients had Hirschsprung's disease (group 1) and 38 had miscellaneous conditions (group 2). The densities of T cells, their subsets expressing surface antigens CD8 and CD4, and T-cell receptors alpha/beta or gamma/beta were measured, as well as densities of mononuclear and epithelial cells expressing HLA-class II antigens. RESULTS: T-cell densities in groups 1 and 2 were similar. Patients with Hirschsprung's disease had significantly more HLA-DR (p = 0.006) and HLA-DP-expressing cells (p = 0.003) in the lamina propria than did the patients in group 2. In group 1, HLA-DR- (r = 0.58; p = 0.46) and HLA-DP-expressing cells (r = 0.66; p = 0.03) showed a significant positive regression with age in the lamina propria, whereas in group 2, HLA-DR+ cells in the lamina propria showed marked (r = -0.9; p = 0.006) negative regression during the first 1.5 months of life. In contrast to results in previous reports, in the current results, HLA-D region antigens were present in the epithelium in a considerable proportion (up to one fourth) of specimens from the large intestine in both groups. CD3+ (r = -0.59; p = 0.006) and CD4+ (r = -0.64; p = 0.002) cells showed a strong negative regression with age in the lamina propria during the first 2.5 months; and thereafter, there was a weak, insignificant rise in the numbers of these cells. The distribution of CD4+, CD8+, and TCR alpha/beta or gamma/beta T cells of the epithelium of the young infants did not differ significantly from that in the epithelium of adults. CONCLUSIONS: These results show that several significant changes occur in the mucosal immune system during the first few weeks of life.

Density of gamma/delta+ T cells in the jejunal epithelium of patients with coeliac disease and dermatitis herpetiformis is increased with age.

Increased density of gamma/delta T cell receptor (TCR)+ intraepithelial lymphocytes is the only characteristic in the jejunum of patients with coeliac disease and dermatitis herpetiformis which is not normalized on a gluten-free diet. We explored the age-dependent changes in intraepithelial gamma/delta and alpha/beta TCR+ cells from 137 biopsies from patients with coeliac disease and dermatitis herpetiformis and from controls. Biopsy specimens from 100 patients with coeliac disease and dermatitis herpetiformis and from 37 controls were studied with an immunohistochemical method using MoAbs to T cell receptors and peroxidase staining. An increase in the density of intraepithelial gamma/delta T cells above the mean +2 s.d. of the density in controls was present in 97 of 100 specimens from patients with coeliac disease and dermatitis herpetiformis. The density of gamma/delta+ cells of patients with coeliac disease and dermatitis herpetiformis on a normal gluten-containing diet showed a positive correlation with age (r = 0.45, P < 0.0001). In controls, the density of gamma/delta+ cells remained low throughout the age-range studies, from age 0.6-57 years. In controls, alpha/beta+ cells increased with age (r = 0.57, P < 0.001). The increase in density of intraepithelial lymphocytes with age is in agreement with their thymus-independent character and local proliferation.

Immunohistochemical findings in jejunal specimens from patients with IgA deficiency.

Jejunal biopsy specimens from 25 patients with IgA deficiency (IgAd) were studied immunohistochemically to find markers of inflammation. Five of the 25 patients had coeliac disease (CD): they were on a gluten free diet and had normal jejunal morphology. Only two of 15 specimens from control subjects had CD25+ cells in the surface epithelium, while this was seen in 19 out of 20 specimens from IgAd patients (p < 0.0001). A significant increase of CD25+ cells was also noted in the lamina propria of IgAd patients. The median percentage of crypt cells in mitosis (Ki67+ cells) was higher in the specimens from IgAd patients (26%) than in those from controls (13%, p < 0.001). The densities of gamma delta T cell receptor positive cells in the surface epithelium and lamina propria did not differ in the specimens from IgAd patients and those of controls nor was the expression of HLA class II antigens augmented in the surface epithelium. These findings were similar for the IgAd patients whether or not the patient had DQB 0201 allele, a genetic marker which is strongly associated with CD. The inadequacy of the local immunoglobulins in patients with IgAd may lead to increased T cell activation, which is accompanied by the appearance of intraepithelial CD25+ cells and with an increase in the mitotic rate in the crypts.

Prospective evaluation of Candida antigen and antibody assays for detection of Candida infections in children with malignant disease.

The clinical efficacy of assays for Candida albicans antigens by latex agglutination and for antibodies by indirect haemagglutination were prospectively evaluated in the diagnosis of invasive Candida infections in 38 children suffering from acute leukaemia or other malignant disease. The controls were 74 other patients without any malignancy; 72 of these had no signs or symptoms of fungal infections, but 2 had an invasive C. albicans infection. During a period of 21 months, 302 serum samples were tested by both assays, and the results were compared with clinical and other microbiological data. Invasive fungal infection was diagnosed on clinical grounds in 2 of the immunocompromised children, and periodic gut colonization was demonstrated in 11 of 36 (31%) children in this group. Positive Candida antigen was detected in 14 patients (37%) and a positive antibody titre in 7 patients (18%). Colonization was not correlated with antigen or antibody titre. Compared with the presence of invasive fungal infection, the antibody assay detected all four infections, whereas the antigen assay detected one of the two C. albicans septicaemias. Although the Candida antibody assay performed well, a detectable change in antibody titres appeared only slowly. Thus it was of no clinical help when antifungal treatment was to be considered. Follow-up of antibody titres, however, gave confirmation of the presence of fungal infection as well as the response to antifungal treatment.

Exclusive whole protein enteral diet versus prednisolone in the treatment of acute Crohn's disease in children.

Nineteen children with either newly diagnosed or relapsed Crohn's disease were enrolled in a randomized study in which the efficacy of enteral feeding with a whole protein-based formula was compared to high-dose corticosteroids in achieving clinical remission and normalization of laboratory measurements. Ten children were treated by enteral feeding (Nutrison Standard, Nutricia), and nine received corticosteroids. Both treatment regimens lasted 11 weeks. The activity of Crohn's disease was similar in both groups before the commencement of the treatment. Clinical symptoms and signs, as judged by the pediatric Crohn's disease activity index and measurements relating to inflammatory activity (erythrocyte sedimentation rate, C-reactive protein, blood leukocyte and platelet count, and serum immunoglobulins G and A) and to nutritional status (concentrations of serum albumin, prealbumin, hemoglobin) improved rapidly and significantly with as little as 2 weeks' treatment in both treatment groups. In both groups, there was one relapse within 8 weeks after discontinuation of treatment, and one patient in both groups was operated on during the treatment period. During the routine follow-up after the trial (0.3-2.5 years; mean, 1.3 years) five of the corticosteroid group experienced a clinical relapse, whereas only one from the enteral feeding group relapsed. No side effects of enteral feeding were seen. Enteral feeding with a whole protein-based formula proved to be as effective as high-dose corticosteroid in the treatment of the acute phase of Crohn's disease and may prove to be the treatment of choice in pediatric patients with acute Crohn's disease.

Peripheral gamma delta T cell receptor-bearing lymphocytes are increased in children with celiac disease.

The percentages of gamma delta T cell receptor-bearing (TCR+) cells in the peripheral blood and jejunal mucosa of patients with celiac disease were measured before treatment, during a gluten free-diet, and after a gluten challenge. The percentages of the different cell types were evaluated by flow cytometry, and immunohistochemical staining of the jejunal specimen was used to identify lymphocyte surface markers. Nineteen blood samples and intestinal specimens from 13 children with celiac disease (eight samples taken before treatment, six during gluten-free diet, and five after gluten challenge) and samples from nine controls were studied. The proportion of gamma delta TCR+ lymphocytes was significantly higher both in the peripheral blood and the jejunal mucosa of the patients with celiac disease. A significant correlation was found between the percentage of peripheral gamma delta TCR+ cells and the density of gamma delta TCR+ cells in the lamina propria.

Fungal gut colonization with Candida or Pityrosporum sp. and serum Candida antigen in preterm neonates with very low birth weights.

To evaluate the diagnostic value of gut colonization by yeasts and of candida antigen in serum for predicting fungal infection in very premature neonates, faecal and serum samples were obtained biweekly from 27 newborn babies treated at our neonatal intensive care unit. Altogether 82 sets of serum and faecal samples were obtained. 17 babies were followed for > or = 4 weeks. Blood cultures, both by routine and lysis centrifugation techniques, were performed for bacteria and fungi if infection was suspected. All children were given systemic broad-spectrum antibiotic treatment. Five of the children died, all without evidence of fungal infection. No systemic antifungal treatments were given. Quantitative faecal cultures demonstrated Candida albicans in 3 (11%) (10(3)-10(5) colony forming units/g) and Pityrosporum sp. in 8 (30%) of the preterm neonates. Candida antigen in titre 4 was detected in 1/82 serum samples. The child subsequently died with no other evidence of candida infection. In 56 full term neonates treated at the intensive care unit during the same period and tested by 1 set of samples, faecal colonization with Candida sp. was detected in 2 (4%) and with Pityrosporum sp. in 4 (15%). None were positive for candida antigen. Fungal gut colonization did not lead to clinical infection in the preterm neonates studied. The false positivity rate of the candida antigen test was low (0.7%). The predictive value of the test could not be determined in this study group with no systemic fungal infections. The role of pityrosporum as an inducer of neonatal infections remains to be evaluated.