Development of seasonal allergic rhinitis during the first 7 years of life.

BACKGROUND: Against the background of the controversial discussion about an increase in allergic rhinitis in recent years, intraindividual longitudinal data is lacking for IgE-mediated seasonal allergic rhinitis (SAR). Little is known about the development of SAR in terms of prevalence and incidence rates from birth to school age. OBJECTIVE: In a prospective birth cohort, we investigated the development of sensitization and symptoms of SAR. SAR should be defined with high specificity, and associated risk factors should be determined. METHODS: Annual longitudinal data about seasonal allergic symptoms and sensitization was available for 587 children from birth to their seventh birthday. The definition of SAR was based on a combination of exposure-related symptoms and sensitization. RESULTS: Up to 7 years of age, SAR developed in 15% of the children. Incidence and prevalence of symptoms and sensitization were low during early childhood (<2%) and increased steadily with age. Children in which SAR had already developed in the second year all were born in spring or early summer, resulting in at least two seasons of pollen exposure before manifestation of SAR. Risk factors assessed by multiple logistic regression analysis were male sex (odds ratio [OR] = 2.4), atopic mothers (OR = 2.6) and fathers (OR = 3.6) having allergic rhinitis themselves, first-born child (OR = 2.0), early sensitization to food (OR = 3.3), and atopic dermatitis (OR = 2.5), whereas early wheezing was not associated with SAR. CONCLUSION: The development of SAR is characterized by a marked increase in prevalence and incidence after the second year of life. Our longitudinal data further indicate that in combination with the risk of allergic predisposition, at least 2 seasons of pollen allergen exposure are needed before allergic rhinitis becomes clinically manifest.

Glycyl-glutamine improves in vitro lymphocyte proliferation in AIDS patients.

BACKGROUND: Glutamine (Gln) is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for Gln is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glycyl-glutamine on lymphocyte proliferation we investigated its influence on lymphocytes of AIDS patients and healthy controls under stimulation with different mitogens. MATERIAL AND METHODS: Lymphocytes were collected from 11 adult patients suffering from AIDS according to the CDC definition and from 7 adult healthy donors. Glutamine (Gln) and glycyl-glutamine (GlyGln), respectively, were added to cell cultures at concentrations between 0 and 1.0 mmol/l. ConA or SAC served as T or B cell mitogens, respectively. Plasma amino acid levels were determined. RESULTS: Proliferation upon ConA-stimulation with GlyGln-supplementation was similar to Gln-supplementation and peaked dose dependently at 1.0 mmol/l. When SAC was used Gln seemed slightly superior to GlyGln with a peak at 0. 4 mmol/l but the results did not reach the level of statistical significance. An identical response pattern was demonstrated in HIV-patients, however at lower absolute proliferation rates. Normal values could not be restored. Overall, the use of either source of glutamine in equimolar concentrations did not result in major differences of proliferation. Glutamine and glycin plasma levels did not differ between HIV patients and controls. CONCLUSION: GlyGln can be used as a substitute for Gln with regard to lymphocyte proliferation. Lymphocytes from AIDS patients show, as controls do, an enhanced proliferation under supplementation either glutamine source. Supplementation of GlyGln might enhance lymphocyte proliferation and thus improve immunity.

Alpha 1-proteinase inhibitor abrogates proteolytic and secretagogue activity of cystic fibrosis sputum.

Airway disease in cystic fibrosis (CF) is characterized by neutrophil-dominated chronic inflammation with an excess of uninhibited neutrophil elastase (NE), which is regarded as an important factor in progressive lung destruction. Therefore, inhalation of alpha 1-proteinase inhibitor (alpha 1-PI) seems to be a reasonable therapeutic approach. To estimate its therapeutic potential, we quantitatively investigated the in vitro interactions of exogenous alpha 1-PI with CF sputum samples (n = 28). High NE and alpha 1-PI concentrations were detected in CF sputum (6.03 +/- 0.78 and 2.56 +/- 0.16 mumol/l, respectively). There was significant NE activity (2.6 +/- 0.4 U/l) due to both the surplus of NE and proteolytic degradation of alpha 1-PI. Addition of exogenous alpha 1-PI resulted in a dose-dependent inhibition of NE activity in CF sputum; > 90% inhibition was achieved at 10 micrograms/ml alpha 1-PI. Purified NE as well as CF sputum potently induced secretion from porcine tracheal glands. Corresponding to inhibition of NE activity, CF sputum-induced secretion was also inhibited by exogenous alpha 1-PI; > 90% inhibition was also achieved at 10 micrograms/ml alpha 1-PI. Incubation of exogenous alpha 1-PI with CF sputum for 24 h did not reduce the inhibitory effects. From our in vitro results we conclude that inhalation of alpha 1-PI might effectively inhibit both NE activity and airway gland hypersecretion in CF airways.

[High-dose immunoglobulin therapy of hyperbilirubinemia in rhesus incompatibility]. / Hochdosierte Immunglobulintherapie der Hyperbilirubinämie bei Rhesusinkompatibilität.

We conducted a multicenter controlled trial to test the hypothesis that high intravenous doses of immunoglobulin (HDivIg) can modulate the bilirubin production and reduce the frequency of exchange transfusions in newborn infants with rhesus incompatibility. Thirty-four patients with rhesus incompatibility proven by positive direct antiglobulin test (Coombs test) were randomly assigned to conventional treatment including phototherapy, with or without additional HDivIg at 500 mg/kg given over 2 h, as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded the modified curves of Polácek by more than 2 mg/dl. The results in 32 infants were analyzed. In the HdivIg-treated group, 2 of 16 (12.5%) children required exchange transfusions, whereas it became necessary in 11 of 16 (69%) in the control group (p < 0.005). Bilirubin levels in the HDivIg-treated group were lower despite a reduced frequency of exchange transfusions. We conclude that HDivIg by a yet unknown mechanism reduces bilirubin serum levels in children with rhesus incompatibility and the need for exchange transfusions.

[Immunomodulating therapy of systemic juvenile rheumatoid arthritis: administration of high-dose intravenous gamma globulin]. / Immunmodulatorische Therapie der systemischen juvenilen rheumatoiden Arthritis: Einsatz von hochdosiertem intravenös verabreichtem Gammaglobulin.

Two children of 9 and 10 years suffering from severe systemic juvenile rheumatoid arthritis were treated intravenously with high-dose human immunoglobulin. Treatment was performed every 4 weeks for 7 and 18 months, respectively. Improvement of arthritic symptoms was demonstrable by significant decreases of Ritchie index and number of swollen joints and the disappearance of heated joints in one patient. The other patient was free of arthritic symptoms since the introduction of immunoglobulin therapy. Clinical symptoms of systemic illness were markedly improved and no relapse was seen. Laboratory parameters also improved, including erythrocyte sedimentation rate, C-reactive protein, hemoglobin, and serum iron levels. Parallel investigations of immunological parameters revealed a decrease of serum Il-1 beta and Il-6 levels and a diminished in vitro production of Il-1 beta, Il-6, and tumor necrosis factor-alpha. Therefore, we suggest a decreased activation status of the monocyte-macrophage system as one possible mode of action.

[Intravenous immunoglobulins in bronchial asthma: a therapeutic alternative?]. / Intravenös verabreichte Immunoglobuline bei Asthma bronchiale: eine therapeutische Alternative?

Treatment of severe bronchial asthma usually requires the use of steroids. Given the known side effects of steroid treatment, potential alternative therapeutical strategies are currently evaluated; among others, intravenously administered immunoglobulins (ivIg) may be considered. In one study of 5 children with bronchial asthma and IgG subclass deficiency, an improvement of asthma was demonstrated in 4 out of the 5 patients under ivIg treatment over several months. In another study on ivIg treatment in 8 immunocompetent children with steroid-dependent asthma, there also was an improvement of asthma, leading to a reduction in the required steroid dose; furthermore, there was a diminution in skin prick test reactivity. At present, only speculations can be made about the possible mechanisms of action.

Inhibition of adhesion of S-fimbriated E. coli to buccal epithelial cells by human skim milk is predominantly mediated by mucins and depends on the period of lactation.

Expression of S-fimbriae is frequent in Escherichia coli strains causing sepsis and meningitis in the newborn period. We analysed the ability of human skim milk to inhibit adhesion of S-fimbriated E. coli to human buccal epithelia. Adhesion was inhibited by up to 90% using colostrum (5%) and up to 50% with mature milk (5%), indicating that this anti-infective mechanism depends on the period of lactation. Elimination of up to 99% of immunoglobulins and 91% of lactoferrin by affinity chromatography had no effect on the inhibition of adhesion. After separation of high- (> 10 kD) and low-molecular-weight fractions of skim milk, only the fraction > 10 kD was found to be able to inhibit bacterial adhesion. In order to further characterize receptor molecules for bacteria, we investigated binding of isolated S-fimbriae to glycoprotein bands on Western blot strips. Fimbriae mainly bound to a high-molecular-weight band (> 200 kD). According to molecular weight and staining behaviour, this band most likely represents mucins. We conclude that carbohydrate residues on secreted mucins of human skim milk are able to inhibit bacterial adhesion to mucosal surfaces. This could provide protection against neonatal sepsis and meningitis caused by E. coli.

Inhibition of adhesion of S-fimbriated Escherichia coli to buccal epithelial cells by human milk fat globule membrane components: a novel aspect of the protective function of mucins in the nonimmunoglobulin fraction.

We investigated the presence of factors in human milk that inhibit invasion of pathogenic bacteria. The effect of human milk fat globule membrane (HMFGM) components on adhesion of cloned S-fimbriated Escherichia coli to human buccal epithelial cells was analyzed. S fimbriae are a common feature of E. coli strains causing sepsis and meningitis in newborns and are bound to epithelia via sialyl-(alpha-2-3)galactoside structures. Human milk fat globules (HMFG) could be agglutinated by the above-mentioned bacteria. Agglutination could be inhibited by fetuin, human glycophorin, and alpha 1-acid glycoprotein. In addition, pretreatment of HMFG with Vibrio cholerae neuraminidase markedly reduced bacterium-induced agglutinations, indicating the involvement of neuraminic acid-containing glycoproteins. In contrast, lipid droplets of infant formula or artificial lipid emulsions (Intralipid) could not be agglutinated. HMFG were present in stools of breast-fed neonates as shown by indirect immunofluorescence staining with a monoclonal antibody directed against carbohydrate residues present on HMFGM. These HMFG could be agglutinated by bacteria. HMFG inhibited E. coli adhesion to buccal epithelial cells. To further characterize relevant E. coli binding structures, HMFGM components were separated by gel chromatography. The mucin fraction showed the most pronounced inhibitory effect on adhesion of S-fimbriated E. coli to human buccal epithelial cells. Our data suggest that HMFG inhibit bacterial adhesion in the entire intestine and thereby may provide protection against bacterial infection.

[A trial with high-dose gamma globulin therapy in 3 children with hyperbilirubinemia in rhesus incompatibility]. / Versuch einer hochdosierten Gammaglobulintherapie bei 3 Kindern mit Hyperbilirubinämie bei Rhesusinkompatibilität.

The influence of high-dose intravenous gammaglobulin (HDivGG) on the course of hyperbilirubinemia was investigated in three newborn infants with rhesus hemolytic disease. In addition to phototherapy and appropriate hydration all children received gammaglobulin (Polyglobulin N, Tropon-Cutter, Cologne, FRG) at a dose of 500 mg/kg body weight intravenously. All three infants showed a marked decrease in bilirubin levels after HDivGG. In two cases exchange transfusion could be avoided. In the third an elevated bilirubin level after blood exchange dropped following HDivGG, and a further exchange transfusion became unnecessary. The suspected effect of HDivGG in Rhesus incompatibility may be due to a blockade of Fc-receptors of the reticuloendothelial system, which prevents further hemolysis and bilirubin production. We propose, that the efficacy of this new mode of treatment should be evaluated in a controlled study.

[Preventive long-term intravenous immunoglobulin infusion in children with acute lymphatic leukemia. I. Anticomplementary activity of gamma globulin preparations is a function of the preparation and IgG concentration prior to infusions]. / Prophylaktische Langzeit-i.v.-Immunglobulin-Infusion bei Kindern mit akuter lymphatischer Leukämie. I. Die antikomplementäre Aktivität der Gammaglobulinpräparate ist eine Funktion des Präparates und der IgG-Konzentration prae infusionem.

The influence of intravenous gammaglobulin infusions (ivGG) on hemolytic complement function and the concentration of serum C3 and its split product C3dg was studied in 20 children with acute lymphocytic leukemia (ALL) undergoing ivGG prophylaxis. IvGG was infused once monthly over a period of 20 months using two different preparations commercially available. Serum and EDTA-plasma were collected before initiation of ivGG therapy (time 1), after 10 and 20 months (time 2 and 3), before and immediately after the infusions. IvGG was infused in connection with chemotherapy (according to the CoAll 82 protocol). 16 of 60 sera collected prior to infusions contained less than 700 mg/dl IgG. Mean IgG concentrations could be raised to 198 mg/dl (time 1), 219 mg/dl (time 2), and 213 mg/dl (time 3), respectively. -CH 50 prior to infusions was below normal in 15 of 59 sera, afterwards in 25 of 59 sera. AP 50 before (after) infusions was decreased in 29 of 59 (36 of 60) sera, C3 in 18 of 60 (24 of 60) sera. C3dg was slightly elevated in one EDTA-plasma prior to ivGG infusions and in 5 of the plasmas following infusions. IvGG infusions resulted in a significant loss of hemolytic activity of serum complement (p less than 0.01, F-test). The effect was more profound if IgG concentrations before infusions were less than 700 mg/dl, but this was true for only one of the two used ivGG preparations. The long term follow up over two years showed no significant changes of complement functions (F-test), indicating complete recovery of complement function from short term anticomplementary effects.

[Significance of immune complexes in children with severe hemophilia A in substitution treatment with factor VIII concentrates]. / Bedeutung von Immunkomplexen bei Kindern mit schwerer Hämophilie A unter Substitutionsbehandlung mit Faktor VIII-Konzentration.

Sera and EDTA-Plasma of patients with severe Haemophilia A were analysed for immune complexes and the hemolytic activity of complement in relation to Factor VIII replacement, in order to confirm or possibly exclude a relationship to allergic reactions. Immune complexes were isolated by PEG precipitation and quantitated. In addition a solid phase ELISA assay was used to detect complement-binding complexes. Total hemolytic complement activity of the classical and the alternate pathway was measured in addition to the C3 splitproduct C3d. The results obtained from 12 patients with severe Haemophilia A showed slightly increased immune complex titers, no changes of the immune complex levels during Factor VIII replacement and no alteration of the complement system following the infusions. One patient developed an allergic reaction without evidence of complement activation.

[Treatment of juvenile rheumatoid arthritis]. / Behandlung der juvenilen rheumatoiden Arthritis.

Recently interest in pediatric rheumatology has increased. This review tries to summarize our knowledge about pharmacological mechanisms, as well as practical application and adverse of antirheumatic drugs. In addition, forms of treatment which sofar lack any scientific backing are mentioned and discussed. Various data about efficacy and side effects in children are poor or lacking, and current treatment in children is based on analogy conclusions derived from experiences with adult RA. The therapeutic concept presented in this article offers a good chance to improve the functional status of the rheumatic child. However, one should be aware that several controlled trials with antirheumatic drugs in children still have to be performed. Uncertainties have to be replaced by knowledge. This is true also for the surgical treatment mentioned.

Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism.

L-Asparaginase (l-Asp) is widely used as an effective drug against childhood and adult acute lymphoblastic leukemia (ALL). However, it is immunogenic in humans and may lead to hypersensitivity reactions. The immunological basis of these reactions is not clear. Since the presence of l-Asp specific IgG-antibodies seems to correlate better with clinical reactions than IgE-antibodies and IgG-antibodies are known to be able to fix and activate the complement system, we speculated that the mechanism of anaphylaxis may be complement- rather than IgE-mediated. We analyzed 24 children with ALL (age 2-15 yr) for changes in the complement system during l-Asp infusions. Chemotherapy was administered according to the CoALL 82 protocol which is derived from the CoALL 80 protocol recently published. The formation of specific antibodies of IgM and IgG classes against l-Asp was monitored by a solid phase ELISA. The immunological responsiveness of individual patients varied over a wide range but both types of antibodies were induced. Anaphylactic reactions were observed on eight occasions in eight children. The infusions in the remaining 16 patients were tolerated without clinical reactions. Significant activation of complement was demonstrated in seven of eight reaction occasions and in none of the occasions without reactions. The most important complement activation parameter monitored was the C3 split product C3d measured in EDTA-plasma. We conclude that anaphylaxis to l-Asp in patients with ALL can be explained in most instances on the basis of complement activation induced by the formation of immune complexes of l-Asp and specific antibodies of IgM and IgG classes.