Disseminated Mycobacterium scrofulaceum infection in a child with interferon-gamma receptor 1 deficiency.

Disseminated disease caused by non-tuberculous, environmental mycobacteria (EM) reflects impaired host immunity. Disseminated disease caused by Mycobacterium scrofulaceum has primarily been reported in patients with AIDS. Moreover, observing M. scrofulaceum as the agent of localized disease in childhood has become increasingly rare. We report the first case of disseminated disease caused by M. scrofulaceum in a child with inherited interferon-gamma receptor 1 (IFN-gammaR1) complete deficiency. As in this case, mycobacterial bone infections in IFN-gammaR1 deficiency can sometimes mimic the clinical picture of chronic recurrent multifocal osteomyelitis.

Epithelial cells and fibroblasts: structural repair and remodelling in the airways.

Extensive lesions and changes in the architecture of the airway walls are commonly described in patients with respiratory infections, asthma, chronic bronchitis and interstitial lung diseases. Current knowledge identifies in airway epithelial cells and in fibroblasts the two cell types mainly involved in tissue repair after injury. During inflammatory respiratory disorders, extensive injury of airway epithelium may occur, with shedding of a large sheet of damaged cells in the bronchial and alveolar lumen but also with activation of the surviving epithelial cells and of the underlying fibroblasts. Indeed, besides acting as a physical and functional barrier to external agents, the epithelial surface of the bronchi has the capability to modulate the repair processes through the secretion of extracellular matrix proteins and the interaction with interstitial fibroblasts. Besides releasing pro-inflammatory cytokines and chemokines, the surviving epithelial cells and the underlying fibroblasts secrete factors contributing to airway repair, including the formation of the provisional extracellular matrix. This is indeed the substrate to which the epithelial cells at the edge of the lesion can attach to migrate in order to reconstitute the surface layer. In these processes airway epithelial cells receive the support of bronchial wall fibroblasts which actively release cytokines stimulating epithelial cell functions.

The wheezy infant -- immunological and molecular considerations.

Most of the data on the pathogenesis of asthma is based on information obtained through bronchial biopsies and bronchoalveolar lavage in adults and young adults. Ethical considerations linked to the invasive nature of airway endoscopy have limited the studies on the pathophysiology of asthma in infancy and early childhood. Although there is evidence that an asthma-like inflammation, with increased inflammatory cells and thickening of the lung basement membrane, may be present also at a very early age, clinical and epidemiologic studies suggest that asthma manifestations in preschool children may significantly differ from those observed in older subjects. In western countries, the vast majority of infants and young children has episodic (or intermittent) asthma, and the exacerbations generally defined "wheezing episodes" occur more frequently with a seasonal pattern being usually related to acute viral infections. There is strong epidemiological evidence that approximately 2/3 of all children who wheeze because of viral infections in early life (and are not atopic) have a transient condition that tends to disappear during early school years. All respiratory viruses may be implicated in the wheezing episodes, the principal being respiratory syncytial virus (RSV) and, with a lower frequency, adenovirus and parainfluenza viruses during the first 3 years of life, and rhinoviruses after that age. Infants and preschool children have on average 6-8 "colds" per year, but the illness tends to be limited to the upper respiratory tract alone in a considerable proportion of individuals, without causing symptomatic involvement of the lower respiratory tract. The variety of factors determining the different outcomes are only partially known, but complex interactions between the intrinsic pathogenicity of the virus and host factors, including the socio-economic conditions of the family, are central to define the type of manifestations and the severity of the process.

Correlations between exhaled nitric oxide levels, blood eosinophilia, and airway obstruction reversibility in childhood asthma are detectable only in atopic individuals.

The aim of this study was to compare in atopic and nonatopic asthmatic children correlations between two inflammation parameters, i.e., blood eosinophilia and exhaled nitric oxide (FE(NO)), and pulmonary function values, at baseline and after beta(2)-adrenergic bronchodilators. Ninety-two steroid-naive asthmatic children were evaluated: 26 were skin prick test- and RAST-negative (nonatopic subjects), whereas 66 were atopic, 15 being sensitized only to house dust mites (monosensitized) and 51 to mites and to at least one other class of allergens (polysensitized). Baseline spirometric values (FEV(1) and FEF(25-75%)) were similar in atopic and nonatopic groups (P > 0.1, each comparison). However, when compared to nonatopic subjects, atopic children showed a significantly higher degree of blood eosinophilia (3.0% and 6.7% white blood cell count, respectively; P = 0.0001) and higher FE(NO) levels (6.8 ppb and 16.0 ppb, respectively; P = 0.0001). While a positive correlation between FE(NO) levels and blood eosinophilia was observed in atopic children (r = 0.25, P = 0.041), no correlations between these two inflammation parameters and baseline pulmonary function values were demonstrated in any of the asthmatic groups. Inhalation of a beta(2)-agonist drug induced in the two asthmatic populations similar improvements in FEV(1) and FEF(25-75%) and no changes in FE(NO) levels or blood eosinophilia. However, only in atopic children positive correlations were found between percent variation in FEV(1) (delta%FEV(1)) and FE(NO) levels (r = 0.35, P = 0.006) or blood eosinophilia (r = 0.26, P = 0.04). Within the atopic group, no differences were found between mono- and polysensitized individuals in all parameters evaluated. Thus only in atopic children did parameters of inflammation correlate with airway obstruction reversibility.

Naturally occurring immune response against bacteria commonly involved in upper respiratory tract infections: analysis of the antigen-specific salivary IgA levels.

Lyophilized bacterial lysates, which actively stimulate the immune response, are widely used as vaccines or 'biological response modifiers' in subjects with recurrent bacterial respiratory infections. Since vaccines are indicated in the absence or in the presence of a weak constitutive immune response activity, a better knowledge on the 'naturally' occurring antibacterial immune response at the oropharingeal level should be helpful. A study was, therefore, designed to quantify the presence of salivary IgA directed against surface antigens bacteria frequently involved in the pathogenesis of upper respiratory tract infections: Klebsiella pneumoniae (KP), Staphylococcus aureus (SA), Streptococcus pyogenes (SPy), Morraxella catarrhalis (MC), Haemophylus influenzae (HI), and Streptococcus pnumoniae (SPn). In 34 volunteers (21 adults and 13 children), salivary fluid was collected and the presence of microorganism-specific IgA antibodies evaluated by a novel enzyme immuno-assay. In the whole population only 29 and 24% of subjects had IgA directed, respectively, to KP and SA, while the immune-response against other microbes was detectable in a small population ranging from 12 to 15% of all subjects studied. We found higher proportions of individuals with strain specific salivary IgA in the adult than in the pediatric population for all the microorganism evaluated. In addition, in children, the only strain inducing a significant production of specific IgA at oropharingeal level was KP. Interestingly, only ten out of 21 adults and two out 13 children have at least one significantly high antibody titer against one of the bacteria evaluated. Nevertheless, when a group of healthy donors was treated with a polyvalent mechanical bacterial lysate (Ismigen t.), the large majority developed a specific immune-response in the salivary fluid. These results are thus consistent with the good features of the novel enzyme-immunoassay and with a poor frequency of naturally induced specific anti-microbe antibodies in children and in adults despite the presence on recurrent respiratory infections in their clinical history.

Fibroblast-eosinophil interaction: modulation of adhesion molecules expression and chemokine release by human fetal lung fibroblasts in response to IL-4 and TNF-alpha.

In addition to be involved in airway remodelling observed in asthmatic patients, lung fibroblasts may directly contribute to pulmonary inflammation through the release of mediators and through the expression of surface molecules involved in cell-cell interaction. The aim of the study was to evaluate whether two cytokines involved in asthma pathogenesis, IL-4 and TNF-alpha, could modulate the expression of adhesion molecules (VCAM-1 and ICAM-1) and the secretion of chemokines (eotaxin and MCP-1) related to eosinophil recruitment and activation. The constitutive expression of VCAM-1 by unstimulated fibroblasts was over 2-fold lower than that of ICAM-1 (P<0.05). Significant differences were also observed in the release of chemokines by unstimulated fibroblast, the levels of eotaxin being over 17-fold lower than those of MCP-1. Stimulation of the cells with IL-4 or TNF-alpha induced a dose-dependent increase in VCAM-1, while ICAM-1 was overexpressed only in culture stimulated by TNF-alpha (P<0.05) but not in those exposed to IL-4 (P>0.05 each comparison). In contrast, a significant increase in MCP-1 and eotaxin release was observed in the presence of TNF-alpha (P<0.05) but not of IL-4 (P>0.05). These data show that two 'proinflammatory' cytokines, such as IL-4 and TNF-alpha, may have different and complementary effects on functions involved in the cross-talking between fibroblasts and eosinophils.