Background Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function.Methods The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death.The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra). FindingsFrom March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0•22 [95% CI 0•11-0•41; p<0•0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR 0•22 [95% CI 0•10-0•49]; p=0•0002). An increase in liver aminotransferases occurred in seven (13%) patients in the anakinra group and four (9%) patients in the historical group.Interpretation Anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. Confirmation of efficacy will require con trolled trials.

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Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains. F-X. Blanc, C. Coirault, S. Salmeron, D. Chemla, Y. Lecarpentier. #ERS Journals Ltd 2003. ABSTRACT: The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats.Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxley9s equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (y46% and y42%, respectively), whereas peak isometric tension was similar.The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (y-46% and -34%, respectively).In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity. Asthma is characterised by chronic inflammatory disorders of the airways associated with increased airway responsiveness to various stimuli [1]. The mechanisms underlying nonspecific airway hyperresponsiveness (AHR) remain poorly understood. Although it is clear that airway smooth muscle (ASM) is the key effector of excessive airway narrowing in asthma, it remains unclear whether or not AHR is attributable to ASM abnormality [2,3]. The amount of ASM has been reported to be increased in human asthmatics [4][5][6] and in animal models of AHR [7]. However, recent stereological studies using axial airway sections at high resolution have provided no evidence of increased ASM in large airways of human asthmatics [8]. Marked differences in isotonic contractile properties of isolated ASM have been reported in human asthmatic [9], and in human-[10] and animal-sensitised [11][12][13][14] tissues. In these studies, isolated ASM was found to shorten more and faster in asthmatic and sensitised tissues than in controls without any differences in the ability to generate force. Taken together, these findings suggest functional changes resulting in increased ASM shortening capacity and velocity in hyperresponsive airways, without increases in the amount of ASM [8] or in ASM force production capacity. Potential mechanisms involved in such an increased ASM shortening capacity and velocity include reduced bronchial stiffness [9], decreased resistance to internal shortening [15], and increased myosin crossbridge (CB) cycling rate possibly related to an increased content of smooth-muscle myosin light-chain kinase (smMLCK...

In a multicenter, randomized, double-blind study, we compared the effects of nebulized (5 mg x 2) and intravenous (0.5 mg) albuterol (salbutamol) over 1 h in 47 patients admitted to hospital with severe acute asthma defined as a peak expiratory flow (PEF) below 150 L/min and hypercapnia (Pa(CO2) > or = 40 mm Hg). Additional treatment included nasal oxygen and hydrocortisone succinate. The efficacy was assessed after 1 h. In the group treated by nebulization (NEB group, n = 22) 19 (86%) patients (95% confidence interval: 65 to 97%) had been treated successfully according to predefined criteria, versus 12 (48%) patients (95% confidence interval: 28 to 69%) in the intravenously treated group (i.v. group, n = 25), p = 0.006. The mean increase in PEF was greater in the NEB group than in the i.v. group (+107 +/- 94 L/min versus +42 +/- 66 L/min, p = 0.01) as well as the decrease in Pa(CO2) values (-10 +/- 5 mm Hg versus -2 +/- 12 mm Hg, p < 0.01). Beta agonist-induced hypokalemia was more pronounced in the i.v. group than in the NEB group. We conclude that, in hypercapnic acute asthma, the nebulized route has a greater efficacy and fewer side effects than the intravenous route.

It has been suggested that pulmonary artery pressure at the end of ejection is close to mean pulmonary artery pressure, thus contributing to the optimization of external power from the right ventricle. We tested the hypothesis that dicrotic notch and mean pulmonary artery pressures could be of similar magnitude in 15 men (50 +/- 12 yr) referred to our laboratory for diagnostic right and left heart catheterization. Beat-to-beat relationships between dicrotic notch and mean pulmonary artery pressures were studied 1) at rest over 10 consecutive beats and 2) in 5 patients during the Valsalva maneuver (178 beats studied). At rest, there was no difference between dicrotic notch and mean pulmonary artery pressures (21.8 +/- 12.0 vs. 21.9 +/- 11.1 mmHg). There was a strong linear relationship between dicrotic notch and mean pressures 1) over the 10 consecutive beats studied in each patient (mean r = 0.93), 2) over the 150 resting beats (r = 0.99), and 3) during the Valsalva maneuver in each patient (r = 0.98-0.99) and in the overall beats (r = 0.99). The difference between dicrotic notch and mean pressures was -0.1 +/- 1.7 mmHg at rest and -1.5 +/- 2.3 mmHg during the Valsalva maneuver. Substitution of the mean pulmonary artery pressure by the dicrotic notch pressure in the standard formula of the pulmonary vascular resistance (PVR) resulted in an equation relating linearly end-systolic pressure and stroke volume. The slope of this relation had the dimension of a volume elastance (in mmHg/ml), a simple estimate of volume elastance being obtained as 1.06(PVR/T), where T is duration of the cardiac cycle. In conclusion, dicrotic notch pressure was of similar magnitude as mean pulmonary artery pressure. These results confirmed our primary hypothesis and indicated that human pulmonary artery can be treated as if it is an elastic chamber with a volume elastance of 1.06(PVR/T).