Comel-Netherton syndrome: A local skin barrier defect in the absence of an underlying systemic immunodeficiency.

BACKGROUND: Comel-Netherton syndrome (NS) is a rare autosomal disease, characterized by severe skin disease, hair shaft defects, atopic diathesis, and increased susceptibility for skin infections. Since patients with NS suffer from recurrent infections, it has been hypothesized that an underlying immunodeficiency attributes to this. Here, we studied clinical and immunological characteristics of the cohort of NS patients in the Netherlands in order to identify whether potential immunodeficiencies result in the increased risk of infectious complications. METHODS: Phenotypes were scored for severity of skin condition, specific hair shaft defects, atopy, and recurrent infections. Patients' blood samples were collected for quantification of serum immunoglobulin (Ig) levels, specific antibodies against Streptococcus pneumoniae, and allergen-specific IgE, as well as detailed immunophenotyping of blood leukocyte and lymphocyte subsets by flow cytometry. RESULTS: A total of 14 patients were included with age range 3-46 years and varying degrees of skin involvement. All patients presented with atopic symptoms (food allergy, n = 13; hay fever, n = 10; asthma, n = 7). Recurrent skin infections were common, particularly in childhood (n = 12). Low levels of specific antibodies against S pneumoniae were found in 10 of 11 evaluated patients. Detailed immunological analysis was performed on 9 adult patients. Absolute numbers of lymphocyte subsets and serum immunoglobulin levels were all within normal ranges. CONCLUSION: Multidisciplinary evaluation of our national cohort showed no evidence for a severe, clinically relevant systemic immunodeficiency. Therefore, we conclude that in Dutch NS patients the increased risk of infections most likely results from the skin barrier disruption and that increased allergen penetration predisposes to allergic sensitization.

Specific celiac disease antibodies in children on a gluten-free diet.

OBJECTIVE: Celiac disease (CD) is characterized by histologic alterations in small bowel biopsies. Circulating specific CD antibodies at the time of diagnosis and their disappearance after a gluten-free diet support the diagnosis of CD. We aimed to determine the behavior of the CD antibodies immunoglobulin A anti-tissue transglutaminase (anti-TG2) and immunoglobulin A endomysium (EMA) in children with CD after starting a gluten-free diet. METHODS: This was a retrospective multicenter study in the Netherlands between 2001 and 2009. Inclusion criteria were all newly diagnosed patients with CD younger than 19 years who had at least 1 anti-TG2 and/or EMA measurement before and after starting a gluten-free diet. Eight different anti-TG2 kits were used with substrates of guinea pig TG2 in 1 (Sigma) and 7 human-recombinant TG2: Varelisa and EliA Celikey Phadia-GmbH; Orgentec Diagnostica-GmbH; Diarect AG; Roboscreen GmbH; Aeskulisa Diagnostics; Binding Site Ltd. EMA was analyzed with indirect immunofluorescence tests. Statistical analyses were performed by using mixed-model repeated measurements and survival analysis. RESULTS: There were 129 children with CD included (mean age: 5.6 years; SD ± 4.2). The mean concentration of anti-TG2 decreased significantly within 3 months after starting a gluten-free diet (P < .0001). The cumulative percentage of children who became negative for EMA after ½, 1, 1½, and 2 years was 31%, 60%, 74%, and 87%, respectively. For anti-TG2, a comparable trend was shown: 35%, 55%, 64%, and 78%, respectively. CONCLUSIONS: Doctors taking care of children with CD should be aware that the mean concentration of anti-TG2 will show a 74% decrease (95% confidence interval: 69%-79%) after 3 months of gluten-free diet, and ∼80% of the children will be sero-negative for EMA and anti-TG2 after 2 years of the diet.

A biopsy is not always necessary to diagnose celiac disease.

OBJECTIVES: Small intestinal histology is the criterion standard for the diagnosis of celiac disease (CD). However, results of serological tests such as anti-endomysium antibodies and anti-tissue transglutaminase antibodies (tTGA) are becoming increasingly reliable. This raises the question of whether a small intestinal biopsy is always necessary. The aim of the present study was, therefore, to investigate whether a small intestinal biopsy can be avoided in a selected group of patients. PATIENTS AND METHODS: Serology and histological slides obtained from 283 pediatric patients suspected of having CD were examined retrospectively. The response to a gluten-free diet (GFD) in patients with a tTGA level ≥ 100 U/mL was investigated. RESULTS: A tTGA level ≥ 100 U/mL was found in 128 of the 283 patients. Upon microscopic examination of the small intestinal epithelium, villous atrophy was found in 124 of these patients, confirming the presence of CD. Three patients had crypt hyperplasia or an increased number of intraepithelial lymphocytes. In 1 patient no histological abnormalities were found. This patient did not respond to a GFD. CONCLUSIONS: Pediatric patients with a tTGA level ≥ 100 U/mL in whom symptoms improve upon consuming a GFD may not need a small intestinal biopsy to confirm CD.

Is gluten challenge really necessary for the diagnosis of coeliac disease in children younger than age 2 years?

OBJECTIVE: In the diagnosis of coeliac disease (CD), gluten challenge is recommended for children under the age of 2 years at initial biopsy. The aim of the study was to investigate the diagnostic yield of gluten challenge in this group of children. PATIENTS AND METHODS: We included children aged 2 years or younger who were analysed for possible CD and who had villous atrophy at initial small bowel biopsy in the period 1993-2004. We subsequently identified all patients who underwent a complete gluten challenge. RESULTS: We identified 333 children with possible CD. In 100 children (30%), a gluten challenge was performed, with the diagnosis being confirmed in 97. Retrospectively, in 2 of the 3 children without mucosal relapse, data available before gluten challenge did not justify the initial diagnosis of CD. In the third patient, transient gluten intolerance could not be excluded. At first biopsy, the 2 children without mucosal relapse had negative serological parameters, whereas the third patient had IgA antigliadin antibodies, but no IgA anti-endomysium antibodies (EMA). Indeed, all of the patients with EMA at diagnosis had a relapse at gluten challenge. CONCLUSIONS: Routine gluten challenge in children younger than 2 years at initial diagnosis of CD has an extremely low diagnostic yield. We suggest that routine gluten challenge in this group of patients is not necessary when patients have villous atrophy in combination with EMA. Therefore, a revision of the current diagnostic criteria has to be considered.

Macrolide-resistant Staphylococcus aureus colonization in cystic fibrosis patients: is there transmission to household contacts?

OBJECTIVES: Patients with cystic fibrosis (CF) are frequently colonized by macrolide-resistant Staphylococcus aureus, a result of maintenance macrolide therapy. As transmission of S. aureus between household contacts is common, we examined the prevalence of macrolide-resistant S. aureus colonization in CF patients on maintenance azithromycin therapy and their household contacts and compared this with the S. aureus macrolide resistance prevalence in the community. PATIENTS AND METHODS: Sixty-five CF patients on maintenance macrolide therapy and 194 household contacts were screened for S. aureus colonization by culturing sputa, cough swabs and nasal swabs. Resistance to macrolide, lincosamide and methicillin was determined by disc diffusion tests. The prevalence of macrolide-resistant S. aureus colonization in both groups was compared with figures from a nationwide study into S. aureus carriership and resistance. To assess possible transmission, genotyping of S. aureus was performed using the spa-typing method. RESULTS: Macrolide resistance among CF patients with S. aureus colonization was 69.6%; 75% of these isolates displayed lincosamide resistance too. Among household contacts, macrolide resistance prevalence did not differ significantly from resistance prevalence in the community (9.6% versus 6.3%; P = 0.358). No methicillin resistance was observed. No identical (macrolide-resistant and -susceptible) S. aureus genotypes were observed between CF patients and their household contacts except for one household, suggesting a probable transmission. CONCLUSIONS: No significant increase in macrolide-resistant S. aureus colonization was observed among household contacts of CF patients on long-term azithromycin therapy. Transmission of macrolide-resistant S. aureus could not be proved by genotyping in the majority of households.

Carotid intima-media thickness is different in large- and small-vessel ischemic stroke: the SMART study.

BACKGROUND AND PURPOSE: The role of athersclerosis in the difference between the pathogenesis of large-vessel disease (LVD) and small-vessel disease (SVD) is a matter of debate. Common carotid artery intima-media thickness (CCA IMT) is a marker of atherosclerosis. Our aim was to compare CCA IMT between SVD and LVD patients. METHODS: Two independent observers classified ischemic stroke or transient ischemic attack as caused by SVD or LVD, primarily based on imaging and in addition on clinical features. Mean CCA IMT was calculated based on 6 measurements for each patient. RESULTS: Four hundred and seventeen patients were classified LVD and 115 SVD. Mean CCA IMT was higher in patients with LVD (1.08 mm) than in patients with SVD (0.92 mm). The crude mean difference was 0.16 mm (95% CI, 0.09 to 0.23). After adjustment for age, sex and hypertension, the mean difference was 0.11 mm (95% CI, 0.05 to 0.18). CONCLUSIONS: CCA IMT is higher in LVD patients than in SVD patients supporting the hypothesis that LVD and SVD have a different pathogenesis.