Pierre Scheinmann

Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma

BACKGROUND A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma. METHODS We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life. RESULTS Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10(-5) for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5x10(-5) for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8x10(-6); P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure). CONCLUSIONS This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.

Sublingual‐swallow immunotherapy (SLIT) in patients with asthma due to house‐dust mites: a double‐blind, placebo‐controlled study

A double‐blind, placebo‐controlled study was carried out in 85 patients with a well‐documented history of perennial asthma caused by house‐dust mites. Patients received either placebo or sublingual immunotherapy (SLIT) with a standardized Dermatophagoides pteronyssinus (DP)–D. farinae (DF) 50/50 extract. After a run‐in period, patients received increasing doses up to 300 IR every day for 4 weeks and then three times a week for the following 24 months. The cumulative dose was about 104 000 IR, equivalent to 4.2 mg Der p 1 and 7.3 mg Der f 1. Symptom and medication scores and respiratory function were assessed throughout the trial. Serum specific IgE and IgG4 were determined before SLIT (t0) and after 6 (t1), 11 (t2), 17 (t3), and 25 months (t4) of SLIT. Mite exposure was evaluated at t0, t2, and t4 by semiquantitative guanine determinations. Patients aged 15 years and older were asked to assess their quality of life (QoL) by completing the SF20 (Short Form Health Status Survey) plus two items at t0, t2, and t4. Use of inhaled corticosteroids and β2‐agonists was significantly decreased after 25 months of treatment in both groups (P<0.03). SLIT patients showed significant improvements in respiratory function at t4 (% predicted FEV1 (P=0.01), VC (P=0.002), morning (P=0.01) and evening (P=0.03) PEFR), and reduction in daytime asthma score (P=0.02). In the SLIT group, the post‐treatment PD20 was 1.75 times higher than the baseline value. There was no change in PD20 in the placebo group. Compared to the placebo group, the SLIT group showed a significant increase in specific IgE DP (P=0.05), IgE DF (P=0.02), IgG4 DP (P=0.001), and IgG4 DF (P=0.001) levels after SLIT. QoL scores were similar in both groups at t0 and t2. At t4, all scores were better in the SLIT group than in the placebo group, with the differences being most marked for the general perception of health (P=0.01) and physical pain (P=0.02). Adverse events were similar in the two groups. This study shows that SLIT in house‐dust‐mite‐related asthma has a good safety profile and improves respiratory function, bronchial hyperreactivity, and QoL.

Efficacy of nebulized budesonide in treatment of severe infantile asthma: A double-blind study

BACKGROUND AND OBJECTIVE Treatments with inhaled corticosteroids yielded conflicting results in infants with severe asthma. The purpose of this study was to assess the efficacy of nebulized budesonide on the control of asthma in this age group. METHODS In a double-blind, placebo-controlled study, 40 infants with severe asthma received either nebulized budesonide (1 mg) or placebo twice daily for 12 weeks, followed by a follow-up period of up to 12 weeks. A jet nebulizer driven by an air compressor was used to administer budesonide and placebo. RESULTS Fewer patients in the budesonide group had an exacerbation during the treatment period (40%) compared with the placebo group (83%, p < 0.01). The duration of oral steroid therapy was shorter in the budesonide group than in the placebo group (median number of days of exacerbation as a proportion of the total treatment time, 0% vs 14.5%; p < 0.05). The incidence of daytime (p < 0.05) and nighttime wheezing (p < 0.01) was lower in the budesonide group than in the placebo group during the treatment period. The proportion of patients without an exacerbation of asthma during the entire 24 weeks was 28% for those patients who had received budesonide and 0% for those patients who had received placebo. Asthma improved in more patients in the budesonide group (17 and 19, 89%) than in the placebo group (7 of 16, 44%; p < 0.005). These results should improve and modify the treatment of infants with severe asthma. CONCLUSION Nebulized budesonide (1 mg twice daily) is a well-tolerated and efficient treatment for severe infantile asthma.

DC-SIGN Induction in Alveolar Macrophages Defines Privileged Target Host Cells for Mycobacteria in Patients with Tuberculosis

Background Interplays between Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) in human and host professional phagocytes, namely macrophages (Mφs) and dendritic cells (DCs), are central to immune protection against TB and to TB pathogenesis. We and others have recently shown that the C-type lectin dendritic cell–specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209) mediates important interactions between mycobacteria and human monocyte-derived DCs (MoDCs) in vitro. Methods and Findings In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB (n = 40) or with other non-mycobacterial lung pathologies, namely asthma (n = 14) and sarcoidosis (n = 11), as well as from control individuals (n = 9). We show that in patients with TB, up to 70% of alveolar Mφs express DC-SIGN. By contrast, the lectin is barely detected in alveolar Mφs from all other individuals. Flow cytometry, RT-PCR, and enzyme-linked immunosorbent assay analyses of BAL-derived fluids and cells indicated that M. tuberculosis infection induces DC-SIGN expression in alveolar Mφs by a mechanism that is independent of Toll-like receptor-4, interleukin (IL)-4, and IL-13. This mechanism most likely relies on the secretion of soluble host and/or mycobacterial factors that have yet to be identified, as both infected and uninfected bystander Mφs were found to express DC-SIGN in the presence of M. tuberculosis. Immunohistochemical examination of lung biopsy samples from patients with TB showed that the bacilli concentrate in pulmonary regions enriched in DC-SIGN-expressing alveolar Mφs in vivo. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN–expressing alveolar Mφs constitute preferential target cells for M. tuberculosis, as compared to their DC-SIGN− counterparts. In contrast with what has been reported previously in MoDCs in vitro, ex vivo DC-SIGN ligation by mycobacterial products failed to induce IL-10 secretion by alveolar Mφs, and IL-10 was not detected in BALs from patients with TB. Conclusion Altogether, our results provide further evidence for an important role of DC-SIGN during TB in humans. DC-SIGN induction in alveolar Mφs may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.

Microbiological Diagnosis of Empyema in Children: Comparative Evaluations by Culture, Polymerase Chain Reaction, and Pneumococcal Antigen Detection in Pleural Fluids

BACKGROUND Pleural empyema is an increasingly reported complication of pneumonia in children. Microbiological diagnostic tests for empyema by culture frequently have false-negative results due to previous administration of antibiotics. Molecular diagnosis by broad-range 16S ribosomal DNA (rDNA) polymerase chain reaction (PCR) and rapid pneumococcal antigen detection are reliable tools, but their diagnostic value has not been clearly established for pleural fluid samples. Pneumococcal antigen detection has only been validated for urine and cerebrospinal fluid samples. METHODS Over 4 years, pleural fluid specimens were collected from 78 children with pleural empyema. Standard culture, pneumococcal antigen detection by latex agglutination (Pastorex; Bio-Rad) and immunochromatographic testing (Binax NOW Streptococcus pneumoniae), and 16S rDNA PCR were performed on these specimens. Pneumococcal identification by 16S rDNA PCR and sequencing was confirmed by pneumolysin PCR. RESULTS Of the 78 cases of pleural empyema, 60 (77%) were microbiologically documented by culture or 16S rDNA PCR. Of the 40 pneumococcal empyema cases, 17 (43%) were only diagnosed by PCR and 23 with PCR and culture. The sensitivity and specificity of the latex antigen detection (with the use of culture and/or PCR as the test standard) were 90% and 95%, respectively. The immunochromatographic test detected pneumococcal antigens in 3 additional specimens for which latex agglutination results were negative, thereby increasing the sensitivity of antigen detection. CONCLUSIONS Pneumococcal antigen detection in pleural fluid specimens from children provides a rapid and sensitive method of diagnosis of pneumococcal empyema, which can be confirmed by specific pneumolysin PCR when culture results are negative. Broad-range 16S rDNA PCR has value in detecting bacterial agents responsible for culture-negative pleural empyema.

Spontaneous pneumomediastinum in children.

Summary. Spontaneous pneumomediastinum (SPM) is rare in children, mainly affecting male adolescents. It is usually secondary to alveolar rupture in the pulmonary interstitium, followed by dissection of gas towards the hilum and mediastinum. Many pathological and physiological events can lead to alveolar rupture, but the most common cause in children is asthma. The clinical diagnosis is based on the symptom triad of chest pain, dyspnea, and subcutaneous emphysema, and is also based on Hammans sign. The diagnosis is confirmed by chest radiography. The main differential diagnosis is esophageal perforation, which requires an esophagogram with contrast when there is the slightest doubt in the diagnosis. Spontaneous pneumomediastinum generally resolves spontaneously within a few days, meaning that ambulatory treatment is usually appropriate. Management consists of treating the underlying cause (if identified), rest, analgesics, and simple clinical monitoring. Predisposing factors should be identified and controlled to prevent recurrence. Cases of idiopathic SPM necessitate diagnostic pulmonary function tests after the acute episode, to establish whether the child has asthma. Pediatr Pulmonol. 2001; 31:67–75.

Mycobacterium abscessus and children with cystic fibrosis.

We prospectively studied 298 patients with cystic fibrosis (mean age 11.3 years; range 2 months to 32 years; sex ratio, 0.47) for nontuberculous mycobacteria in respiratory samples from January 1, 1996, to December 31, 1999. Mycobacterium abscessus was by far the most prevalent nontuberculous mycobacterium: 15 patients (6 male, 9 female; mean age 11.9 years; range 2.5–22 years) had at least one positive sample for this microorganism (versus 6 patients positive for M. avium complex), including 10 with >3 positive samples (versus 3 patients for M. avium complex). The M. abscessus isolates from 14 patients were typed by pulsed-field gel electrophoresis: each of the 14 patients harbored a unique strain, ruling out a common environmental reservoir or person-to-person transmission. Water samples collected in the cystic fibrosis center were negative for M. abscessus. This major mycobacterial pathogen in children and teenagers with cystic fibrosis does not appear to be acquired nosocomially.

Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures

Although several studies have demonstrated the efficacy of subcutaneous immunotherapy in allergic asthma, few have shown the same benefit using sublingual immunotherapy (SLIT) in asthmatic patients. This study was conducted to assess the efficacy of house dust mite (HDM) SLIT in addition to allergen avoidance and standard pharmacologic treatment. A double‐blind, placebo‐controlled trial was performed in 111 children (aged 5–15 yr) with HDM‐induced mild‐to‐moderate asthma. After a 4‐week baseline phase, patients were randomly assigned to receive SLIT with tablets of HDM extract (n = 55) or placebo (n = 56) for 18 months. Pharmacologic treatment was adjusted every 3 months following a step‐down approach. Asthma symptom scores, reduction in use of inhaled corticosteroids and inhaled β2‐agonists, rhinitis symptoms, lung function tests, skin sensitivity to HDM, dust mite‐specific immunoglobulin (Ig) E and IgG4, and quality of life (QoL) were assessed during the study. After 18 months of treatment, diurnal and nocturnal asthma symptoms scores did not show significant differences between SLIT and placebo groups. Inhaled corticosteroids and inhaled β2‐agonists use was reduced in both groups without significant differences between groups. There were no significant differences in lung function (forced expiratory volume in 1 s and peak flow rate variations) between groups. Rhinitis symptom score decreased in both groups, with no difference between the two groups. The severity dimension of QoL was significantly improved in the SLIT group (age 6–12 yr). SLIT induced a significant reduction of skin sensitivity to HDM (p < 0.01) and a significant increase in HDM‐specific IgE and IgG4 antibodies (p < 0.001) in the SLIT group compared with the placebo group. SLIT was well tolerated with mild/moderate local adverse events. No severe systemic reactions were reported. This study indicates that, when mild–moderate asthmatic children are optimally controlled by pharmacologic treatment and HDM avoidance, SLIT does not provide additional benefit, despite a significant reduction in allergic response to HDM. Under such conditions, only a complete, but ethically unfeasible, discontinuation of inhaled corticosteroid would have demonstrated a possible benefit of SLIT.

Airway remodeling is correlated with obstruction in children with severe asthma.

Background:  Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern.

Allergy to β-Lactam Antibiotics in Children

Background. Skin tests with soluble β-lactams can be used to diagnose immediate and delayed hypersensitivity (HS) reactions to β-lactam antibiotics. Very few studies have been performed with children with suspected β-lactam allergy. In these studies, immediate HS to β-lactams was diagnosed by skin tests in 4.9% to 40% of children. The diagnostic and predictive values of immediate responses in skin tests are good, because very few children with negative skin test results have positive oral challenge (OC) test results. Delayed responses in skin tests (intradermal and patch tests) have been reported in adult patients and children suffering with urticaria, angioedema, and maculopapular rashes during treatments with β-lactam antibiotics. However, the diagnostic and predictive values of late responses are unknown. Semi-late responses in skin tests with β-lactams have never been studied in adults or children. Objectives. The aims of this study were to confirm or rule out the diagnosis of allergy to β-lactams in children with histories of adverse reactions to these antibiotics, to determine whether allergic children were sensitized to one or several classes of β-lactams, and to evaluate the frequency and diagnostic value of immediate, accelerated, and delayed responses in skin tests with β-lactam antibiotics in children. Methods. We studied 325 children with suspected β-lactam allergy. Skin tests (prick and intradermal) were performed with soluble forms of the suspected (or very similar) β-lactams and with one or several β-lactams from other classes. The reaction was assessed after 20 minutes (immediate), 8 hours (accelerated), and 48 to 72 hours (delayed). OCs with the suspected β-lactams were performed in patients with negative skin test results, except those with severe serum sickness-like reactions and potentially harmful toxidermias. Results. Skin tests and OCs led to the diagnosis of β-lactam allergy in 24 (7.4%) and 15 (4.6%) of the children, respectively. Thus, only 12% of the children were diagnosed as allergic to β-lactams by means of skin tests and OC. HS to β-lactams was suspected from clinical history in 30 (9.2%) children reporting serum sickness-like reactions and potentially harmful toxidermias. In a few children, we diagnosed food allergy and intolerance to excipients or nonsteroidal antiinflammatory drugs. No cause was found in the other children. Based on skin tests and OC, the prevalences of immunoglobulin E-dependent and of semi-late or delayed sensitizations to β-lactam assessed were similar (6.8% vs 5.2%, respectively). Most immunoglobulin E-dependent sensitizations were diagnosed by means of skin tests (86.4%). In contrast, most semi-late and delayed sensitizations were diagnosed by OC (70.6%). The likelihood of β-lactam allergy was significantly higher for anaphylaxis (42.9% vs 8.3% in other reactions) and immediate reactions (25% vs 10% in accelerated and delayed reactions). Of the children diagnosed as allergic to β-lactam by means of skin tests, OC, and clinical history, 11.7% were sensitized to several classes of β-lactams. The risk was significantly higher in children with anaphylaxis (26.7% vs 7.5% of the children with other reactions) and in children reporting immediate reactions (33.3% vs 8.5% of the children with accelerated and delayed reactions). Finally, age, sex, personal history of atopy, number of reactions to β-lactams, and number of reactions to other drugs were not significant risk factors for β-lactam allergy. Conclusion. The skin tests were safe, and the immediate reaction to skin tests successfully diagnosed allergy to β-lactam antibiotics in children reporting reactions suggestive of immediate HS. In contrast, most accelerated and delayed reactions were diagnosed by OC. Thus, our results suggest that the diagnostic and predictive values of skin tests for nonimmediate HS to β-lactams in children are low. They also strongly suggest that most reactions reported in children are attributable to infectious diseases or interactions between drugs and infectious agents rather than to β-lactam HS. β-lactams, allergy, skin tests, oral challenge, child.