[Genetic susceptibility to infections]. / Genetische Anfälligkeit für Infektionen.

Infectious diseases are among the leading causes of morbidity and mortality worldwide. The spectrum of clinical manifestations of infections is highly variable, ranging from asymptomatic infection or mild illness to rapid progression of disease and death. Twin studies first showed an inheritable component of many infections and epidemiological and genetic studies revealed definite gene loci and polymorphisms for most of the clinically relevant infectious diseases. Reliable genetic markers which represent susceptibility or resistance to infections, prognosis of disease and response to treatment are necessary to define risk populations and to plan therapy regimens. Genetic research can also help in identifying target structures for novel therapy strategies and anitimicrobial agents. In this article the genetic background of important infections is reviewed and examples of successful exploitation of genetic findings and translation into practical medicine are given.

Role of Helicobacter pylori Infection in the treatment and outcome of chronic urticaria.

INTRODUCTION: Chronic urticaria is thought to have numerous causative factors including a large variety of infectious conditions, food intake, and drugs. The impact of Helicobacter pylori infection has been studied with ambiguous results. The aim of this study was to investigate the course of chronic urticaria in H. pylori-positive patients undergoing eradication compared to H. pylori-negative urticaria patients. PATIENTS AND METHODS: We included 74 urticaria patients with positive H. pylori breath test and 74 age- and sex-matched H. pylori-negative controls. All urticaria patients underwent an extensive diagnostic work-up to search for trigger foci. H. pylori-infected patients were submitted to eradication therapy. Mean follow-up time was 58 months. RESULTS: Neither the prevalence of H. pylori nor the eradication therapy had an influence on the clinical course of chronic urticaria. In 81.1% of H. pylori-infected patients at least one additional infectious focus was found. Nevertheless, it could be shown that individuals that described any kind of symptom relief presented with higher serum IgE levels at diagnosis (198.1 vs 115.7 kU/L, p= .027) but this effect was independent of H. pylori infection. CONCLUSIONS: In conclusion there is no evidence that eradication of H. pylori improves the outcome in patients with chronic urticaria. The high rate of spontaneous remission and the coexistence of multiple foci will always obscure the evaluation of any specific antimicrobial therapy.

A functional variant in the CARD4 gene and risk of premature coronary heart disease.

Infection and innate immunity have been suggested as playing an important role in the pathogenesis of atherosclerosis. The recently discovered pattern-recognition receptor (PRR) proteins initiate signalling after host-pathogen interactions and several PRRs, especially the Toll-like receptor 4 (TLR4), have been shown to be involved in the development and progression of atherosclerosis. A new addition to the PRRs is CARD4, a gene that encodes the protein nucleotide-binding oligomerization domain 1 (NOD1) and that seems to be associated with barrier function in chronic inflammatory disorders. Recently, a functional variant in the CARD4 gene, the insertion-deletion polymorphism ND(1)+32656, has been associated with inflammatory barrier diseases (inflammatory bowel diseases and asthma). We analysed the frequencies of this known functional mutation in the CARD4 gene and of the two adjacent variants, rs2075822 and rs2907748, in a German sample of 1440 unrelated early onset coronary heart disease (CHD) patients and healthy controls. Genotype and haplotype data showed no evidence for a significant association of these CARD4 variants with CHD. Our results suggest that the analysed CARD4 mutations do not play a major role in the aetiology of CHD.

Low frequency of colorectal dysplasia in patients with long-standing inflammatory bowel disease colitis: detection by fluorescence endoscopy.

BACKGROUND AND STUDY AIM: Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colonic dysplasias. Dysplastic changes in flat mucosa are likely to be missed by conventional colonoscopy. Endoscopic fluorescence imaging, using 5-aminolevulinic acid (5-ALA) as photosensitizer, has evolved as a new technique to differentiate between normal colonic mucosa and dysplasia. We combined this technique with random biopsies to prospectively evaluate the occurrence of dysplasias in patients with long-standing IBD. PATIENTS AND METHODS: 52 colonoscopies were performed in 42 consecutive patients (n = 28 with ulcerative colitis, n = 11 with Crohn's colitis, n = 3 with indeterminate colitis; mean age 43 years, range 21 - 78) with long-standing IBD colitis (median disease duration 14 years, range 3 - 40). All patients were in clinical remission. Patients were examined using both conventional white light and by fluorescence colonoscopy using oral 5-ALA. Four biopsies were taken every 10 cm from mucosa of normal appearance. In addition, macroscopically suspicious and fluorescence-positive areas were biopsied. RESULTS: A total of 688 biopsies of red-fluorescent (n = 20) and nonfluorescent (n = 662) areas of mucosa were taken. Dysplasia was detected histopathologically in only two of the biopsies. These biopsies were taken from two polypoid lesions which were fluorescence-negative. CONCLUSIONS: The rate of colonic dysplasia in patients with long-standing IBD colitis may be lower than previously reported.

Bacterial and fungal microbiota in relation to probiotic therapy (VSL#3) in pouchitis.

BACKGROUND: The intestinal microbiota plays a critical role in the pathophysiology of pouchitis, a major complication after ileal pouch anal anastomosis in patients with ulcerative colitis. Recently, controlled trials have demonstrated that probiotics are effective in maintenance of remission in pouchitis patients. However, the mechanism by which therapy with probiotics works remains elusive. This study explores the role of the bacterial and fungal flora in a controlled trial for maintenance of remission in pouchitis patients with the probiotic VSL#3 compound. METHODS: The mucosa associated pouch microbiota was investigated before and after therapy with VSL#3 by analysis of endoscopic biopsies using ribosomal DNA/RNA based community fingerprint analysis, clone libraries, real time polymerase chain reaction (PCR), and fluorescence in situ hybridisation. Patients were recruited from a placebo controlled remission maintenance trial with VSL#3. RESULTS: Patients who developed pouchitis while treated with placebo had low bacterial and high fungal diversity. Bacterial diversity was increased and fungal diversity was reduced in patients in remission maintained with VSL#3 (p = 0.001). Real time PCR experiments demonstrated that VSL#3 increased the total number of bacterial cells (p = 0.002) and modified the spectrum of bacteria towards anaerobic species. Taxa specific clone libraries for Lactobacilli and Bifidobacteria showed that the richness and spectrum of these bacteria were altered under probiotic therapy. CONCLUSIONS: Probiotic therapy with VSL#3 increases the total number of intestinal bacterial cells as well as the richness and diversity of the bacterial microbiota, especially the anaerobic flora. The diversity of the fungal flora is repressed. Restoration of the integrity of a "protective" intestinal mucosa related microbiota could therefore be a potential mechanism of probiotic bacteria in inflammatory barrier diseases of the lower gastrointestinal tract.

Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease.

BACKGROUND AND AIMS: The intestinal bacterial microflora plays an important role in the aetiology of inflammatory bowel disease (IBD). As most of the colonic bacteria cannot be identified by culture techniques, genomic technology can be used for analysis of the composition of the microflora. PATIENTS AND METHODS: The mucosa associated colonic microflora of 57 patients with active inflammatory bowel disease and 46 controls was investigated using 16S rDNA based single strand conformation polymorphism (SSCP) fingerprint, cloning experiments, and real time polymerase chain reaction (PCR). RESULTS: Full length sequencing of 1019 clones from 16S rDNA libraries (n = 3) revealed an overall bacterial diversity of 83 non-redundant sequences-among them, only 49 known bacterial species. Molecular epidemiology of the composition of the colonic microflora was investigated by SSCP. Diversity of the microflora in Crohn's disease was reduced to 50% compared with controls (21.7 v 50.4; p<0.0001) and to 30% in ulcerative colitis (17.2 v 50.4; p<0.0001). The reduction in diversity in inflammatory bowel disease was due to loss of normal anaerobic bacteria such as Bacteroides species, Eubacterium species, and Lactobacillus species, as revealed by direct sequencing of variable bands and confirmed by real time PCR. Bacterial diversity in the Crohn's group showed no association with CARD15/NOD2 status. CONCLUSIONS: Mucosal inflammation in inflammatory bowel disease is associated with loss of normal anaerobic bacteria. This effect is independent of NOD2/CARD15 status of patients.