Viruses and bacteria in acute asthma exacerbations--a GA² LEN-DARE systematic review.

A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.

Lack of association between aspirin-triggered 15-hydroxyeicosatetraenoic acid release and mast cell/eosinophil activation in nasal polyps from aspirin-sensitive patients.

BACKGROUND: The mechanism of aspirin sensitivity in patients with asthma and rhinosinusitis has been attributed to arachidonic acid metabolism abnormalities. OBJECTIVE: We aimed to test whether aspirin-triggered generation of 15-hydroxyeicosatetraenoic acid (15-HETE) in nasal polyp dispersed cells (NPDCs) from aspirin-sensitive patients is associated with activation of inflammatory cells. METHODS: Polyps were obtained from 11 aspirin-sensitive and 19 aspirin-tolerant patients with chronic rhinosinusitis. NPDCs were stimulated by aspirin or calcium ionophore. Levels of 15-HETE, leukotriene (LT) C4, eosinophil cationic protein (ECP), and tryptase were measured in NPDC supernatant. RESULTS: NPDCs from aspirin-sensitive patients contained more eosinophils (14% vs 9%, P < .05) and released 2.4-fold more ECP (P < .01) at baseline. Stimulation with aspirin (200 microM) resulted in a significant increase in 15-HETE generation only in tissue from aspirin-sensitive patients (mean increase, 82%) but did not induce any increase in the release of LTC4, ECP, or tryptase. Preincubation with calcium ionophore resulted in significantly enhanced generation of 15-HETE, ECP, tryptase, and LTC4 in patients from both groups. Incubation of NPDCs with misoprostol inhibited aspirin-induced 15-HETE generation in aspirin-sensitive patients and calcium ionophore-induced 15-HETE, ECP, and tryptase release in both aspirin-sensitive and aspirin-tolerant patients. CONCLUSION: Our study demonstrated that aspirin-induced 15-HETE generation in nasal polyps from aspirin-sensitive patients is not associated with activation of mast cells and eosinophils. Misoprostol has a potent inhibitory effect on the activation of cells derived from the site of nasal mucosal inflammation, regardless of sensitivity to aspirin.

T cell inflammatory response, Foxp3 and TNFRS18-L regulation of peripheral blood mononuclear cells from patients with nasal polyps-asthma after staphylococcal superantigen stimulation.

BACKGROUND: Staphylococcal superantigens may modulate airway inflammatory disease. OBJECTIVE: We assessed the effect of Staphylococcus aureus enterotoxin B (SEB) on T cell activation in patients with nasal polyps and asthma, and its possible link to aspirin hypersensitivity. METHODS: Leucocytes were isolated from five healthy subjects (controls), five asthmatics with nasal polyps without (NP-ATA) and five with aspirin-induced asthma (NP-AIA). Cells were incubated with increasing concentrations of SEB for 4 and 18 h. Release of T(H)1/T(H)2 cytokines was assessed by Cytometric Bead-Array. Foxp3 and TNFRS18-L expression were analysed by qPCR and flow cytometry. RESULTS: After 4 and 18 h, SEB significantly increased IFN-gamma, IL-4, TNF-alpha, IL-5 and IL-2 concentrations in supernatants of both NP polyp groups compared with controls. Baseline Foxp3 was significantly decreased in both NP-asthma groups. Incubation with SEB for 4 h induced a limited up-regulation of Foxp3 in NP-AIA patients, which was switched off consecutively. Foxp3 was significantly up-regulated in the control group after 18 h, but not in the NP-asthmatic groups. In parallel, TNFRS18-L mRNA significantly increased after 18 h in the NP-asthma groups compared with control subjects. This molecule was highly expressed in CD11c(+)CD14(+) cells and its levels increased after 18 and 24 h culture in the NP-asthma patients. CONCLUSION: SEB induces both T(H)1 and T(H)2 pro-inflammatory responses in patients with nasal polyps and asthma regardless of the presence of aspirin hypersensitivity. The nature of this response may be linked to a basal deficiency of Foxp3 observed in the NP-asthmatic patients and/or to the up-regulation of TNFRS18-L on monocytes/dendritic cell precursors.

Involvement of 15-lipoxygenase and prostaglandin EP receptors in aspirin-triggered 15-hydroxyeicosatetraenoic acid generation in aspirin-sensitive asthmatics.

BACKGROUND: The mechanism of aspirin (acetylsalicylic acid: ASA) hypersensitivity in asthmatic patients is related to arachidonic acid metabolism abnormalities, and specific triggering by ASA of 15-hydroxyeicosatetraenoic acid (15-HETE) generation was observed in leucocytes from aspirin-sensitive (AS) but not from aspirin-tolerant (AT) asthmatics. OBJECTIVE: The aim of this study was to identify the enzymatic pathway involved in ASA-induced 15-HETE generation in AS asthmatics and to assess the regulatory role of prostaglandin EP receptors. METHODS: Peripheral blood leucocytes (PBLs) were isolated from AS (n=18) and AT (n=20) asthmatics and challenged with ASA, with and without pre-incubation with caffeic acid (CA) [15-lipoxygenase (15-LO) inhibitor] or prostaglandin receptor non-specific (misoprostol, sulprostone) and specific EP1-4 receptors agonists. Eicosanoids were measured in supernatants using specific immunoassays. RESULTS: Aspirin triggered 15-HETE generation in PBLs of AS asthmatics (mean increase 292%) but not in AT asthmatics and inhibited prostaglandin(2) (PGE(2)) generation in both groups of patients to the same degree. Leucocytes from AS patients produced less PGE(2), both before and after ASA incubation. Pre-incubation of PBLs with CA decreased basal 15-HETE production in all patients and completely inhibited ASA-induced 15-HETE generation in AS asthmatics. CA did not change basal PGE(2) production but enhanced induced by ASA inhibition of PGE(2). Non-specific agonists of EP receptors (misoprostol and sulprostone) did not affect basal 15-HETE production but inhibited in a dose-dependent manner the ASA-induced increase of 15-HETE generation in AS asthmatics. On the contrary, in AT asthmatics, pre-incubation of PBLs with misoprostol or sulprostone resulted in a significant increase in 15-HETE generation after addition of ASA (200 microm). EP1-3 receptor agonists inhibited (range 72-94%) the ASA-induced 15-HETE production significantly. CONCLUSION: Our study demonstrated that ASA-triggered 15-HETE generation involves the activation of 15-LO and is modulated by prostaglandin EP1-3 receptors. The relevance of these observations to the mechanism of in vivo ASA-induced asthmatic attack remains to be established.

Association of stem cell factor expression in nasal polyp epithelial cells with aspirin sensitivity and asthma.

Mast cells constitute a significant proportion of cells infiltrating nasal polyp tissue, and epithelial cells may release stem cell factor (SCF), a cytokine with chemotactic and survival activity for mast cells. We aimed to assess the expression of SCF in human nasal polyp epithelial cells (NPECs) as related to patients' clinical phenotypes. Nasal polyp tissues were obtained from 29 patients [including nine with aspirin (ASA)-hypersensitivity and 12 with bronchial asthma] undergoing polypectomy for nasal obstruction. Epithelial cells were obtained following 6-week culture of nasal polyps explants. The SCF released into the culture supernatant was assessed by enzyme-linked immunosorbent assay (ELISA) and total SCF mRNA in the polyp tissue was determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). For the whole group of patients, the number of polypectomies correlated with expression of SCF mRNA (r = 0.62; P < 0.005), SCF protein in the NPECs supernatants (r = 0.39; P < 0.05) and with density of mast cells in epithelial layer (r = 0.37; P < 0.05) and stromal layer (r = 0.5; P < 0.01) of nasal polyps. The SCF/beta-actin mRNA ratios were significantly higher in ASA-hypersensitive (AH) asthmatics (median 0.97, range: 0.8-1.5) when compared with ASA-tolerant (AT) patients (median 0.5, range: 0.1-0.7; P < 0.001). The SCF protein concentration in NPEC supernatants was also significantly higher in AH asthmatics (median 1.10 pg/microg DNA, range: 0.4-1.9) when compared with AT patients (median 0.1 pg/microg DNA, range: 0.02-1.2; P < 0.001). In the subpopulation of ASA-sensitive asthmatics the number of polypectomies correlated also with the density of mast cells and eosinophils in the polyp tissue.