Endotoxins are potent pro-inflammatory substances present in several natural environments and in commercial house dust extracts. To investigate the possible effect of chronic endotoxin exposure on asthma, 28 patients with perennial chronic asthma (20 allergic to house dust mite and eight intrinsic asthmatics) were evaluated during a 4-month period (lung function, clinical and immunological criteria). At the same time, two house dust samples were collected from each patient's home to determine total house dust weight (mg/m2), endotoxin concentration and house dust mite antigen content (evaluated indirectly by guanine content with HPLC method). The mean (+/- s.d.) endotoxin concentration, as measured by quantitative Limulus assay was 2.59 (+/- 3.41) ng/mg house dust, ranging from 0.12 to 20 ng/mg. The mean guanine content was 0.13 (+/- 0.16) mg/100 mg house dust. There was no correlation between endotoxin and house dust mite concentrations. Patients were compared according to the low or high grade exposure to dust, endotoxins and guanine. Compared with patients with low grade (less than or equal to 5.6 ng/ml) exposure, subjects exposed to high endotoxin concentrations (greater than 5.6 ng/ml) showed a significant increase in dyspnea (median 2.6 vs 3.3; P less than 0.05) and treatment (median 14 vs 44.3; P less than 0.01) scores, oral corticosteroid (median 0.0 vs 13.5 mg/24 hr; P less than 0.01) and beta 2-mimetics (median four vs eight puffs/day; P less than 0.01) intake, and a significant decrease in FEV1/FVC (median 84.5 vs 67% of predicted value; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation of 20 micrograms endotoxins (from the membrane of Gram-negative bacteria) has been reported to induce a bronchial obstructive response in asthmatic subjects. The aim of the present study was to evaluate in asthmatic patients the possibility of an inflammatory response to inhaled endotoxins. Eight patients with mild asthma were submitted to bronchial challenge tests, in a single-blind trial, on Day 1 with control solution and on Day 7 with 20 micrograms endotoxin of Escherichia coli (026:B6). Local inflammatory response was indirectly evaluated by the degree of bronchial hyperresponsiveness (BHR) expressed as PD20 FEV1 histamine (the dose of histamine inducing a 20% decrease in FEV1) at 0, 6, 24, and 48 h and 7 days. Systemic inflammation was investigated by sequential blood determinations of total (and differential) white cells, complement anaphylatoxin C5a, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP). A significant (p < 0.01) bronchial obstructive response was demonstrable 45 min after lipopolysaccharide (LPS) inhalation, lasting 5 h. Comparing the level of BHR after control inhalation, a significant (p < 0.05) increase in BHR was shown 6 h after LPS, partially normalized at 24 and 48 h. A short peak in TNF-alpha at 60 min (p < 0.05) and an increase in total white blood cells (p < 0.01) and neutrophil polymorphonuclear neutrophils at 360 min (p < 0.05) and of CRP at 24 and 48 h (p < 0.05 and p < 0.01) were significant. The other blood parameters did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

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Background Bronchoconstriction has developed after inhalation oflipopolysaccharide in a dose of 20 pg in asthmatic patients and of 200 pg in normal subjects.This study set out to determine whether the bronchial response to lipopolysaccharide was related to non-specific bronchial responsiveness and atopy. Methods Sixteen subjects with a fall in specific airway conductance of 40% (PD.