Dual Effect of Neutrophils on pIgR/Secretory Component in Human Bronchial Epithelial Cells: Role of TGF-β

Neutrophils have a dual affect on epithelial pIgR/SC, the critical receptor for transcellular routing of mucosal IgA, but mechanisms of pIgR/SC upregulation remain elusive. Requirements of cytokine, redox, and signalling pathways for pIgR/SC production were assessed in human bronchial epithelial (Calu-3) cells cocultured with increasing numbers of blood neutrophils. Increased SC production was observed after incubation for 48 hrs with intermediate neutrophil numbers (1.25 to 2.5 × 106), was favoured by the elastase inhibitor SLPI, and correlated with increased TGF-β production. Exogenous TGF-β stimulated SC production with a maximal effect at 48 hrs and both TGF-β- and neutrophil-driven SC upregulation were dependent on redox balance and p38 MAP-kinase activation. This paper shows that activated neutrophils could upregulate epithelial pIgR/SC production through TGF-β-mediated activation of a redox-sensitive and p38 MAPK-dependent pathway. An imbalance between the two neutrophil-driven opposite mechanisms (SC upregulation and SC degradation) could lead to downregulation of pIgR/SC, as observed in severe COPD

Effects of helium-oxygen on respiratory mechanics, gas exchange, and ventilation-perfusion relationships in a porcine model of stable methacholine-induced bronchospasm

Objective: To explore the consequences of helium/oxygen (He/O2) inhalation on respiratory mechanics, gas exchange, and ventilation-perfusion (VA/Q) relationships in an animal model of severe induced bronchospasm during mechanical ventilation. Design: Prospective, interventional study. Setting: Experimental animal laboratory, university hospital. Interventions: Seven piglets were anesthetized, paralyzed, and mechanically ventilated, with all ventilator settings remaining constant throughout the protocol. Acute stable bronchospasm was obtained through continuous aerosolization of methacholine. Once steady-state was achieved, the animals successively breathed air/O2 and He/O2 (FIO2 0.3), or inversely, in random order. Measurements were taken at baseline, during bronchospasm, and after 30min of He/O2 inhalation. Results: Bronchospasm increased lung peak inspiratory pressure (49±6.9 vs 18±1cmH2O, P<0.001), lung resistance (22.7±1.5 vs 6.8±1.5cmH2O.l−1.s, P<0.001), dynamic elastance (76±11.2 vs 22.8±4.1cmH2O.l−1, P<0.001), and work of breathing (1.51±0.26 vs 0.47±0.08, P<0.001). Arterial pH decreased (7.47±0.06 vs 7.32±0.06, P<0.001), PaCO2 increased, and PaO2 decreased. Multiple inert gas elimination showed an absence of shunt, substantial increases in perfusion to low VA/Q regions, and dispersion of VA/Q distribution. He/O2 reduced lung resistance and work of breathing, and worsened hypercapnia and respiratory acidosis. Conclusions: In this model, while He/O2 improved respiratory mechanics and reduced work of breathing, hypercapnia and respiratory acidosis increased. Close attention should be paid to monitoring arterial blood gases when He/O2 is used in mechanically ventilated acute severe asthm

Comparative effects of helium-oxygen and external positive end-expiratory pressure on respiratory mechanics, gas exchange, and ventilation-perfusion relationships in mechanically ventilated patients with chronic obstructive pulmonary disease

Objective: To compare the effects of He/O2 and external PEEP (PEEPe) on intrinsic PEEP (PEEPi), respiratory mechanics, gas exchange, and ventilation/perfusion (V̇A/Q̇) in mechanically ventilated COPD patients. Design and setting: Prospective, interventional study in the intensive care unit of a university hospital. Interventions: Ten intubated, sedated, paralyzed, mechanically ventilated COPD patients studied in the following conditions: (a) baseline settings made by clinician in charge, air/O2, ZEEP; (b) He/O2, ZEEP; (c) air/O2, ZEEP; (d) air/O2, PEEPe 80% of PEEPi. Measurements at each condition included V̇A/Q̇ by the multiple inert gas elimination technique (MIGET). Results: PEEPi and trapped gas volume were comparably reduced by He/O2 (4.2±4 vs. 7.7±4cmH2O and 98±82 vs. 217±124ml, respectively) and PEEPe (4.4±1.3 vs. 7.8±3.6cmH2O and 120±107 vs. 216±115ml, respectively). He/O2 reduced inspiratory and expiratory respiratory system resistance (15.5±4.4 vs. 20.7±6.9 and 19±9 vs. 28.8±15cmH2Ol−1s−1, respectively) and plateau pressure (13±4 vs. 17±6cmH2O). PEEPe increased airway pressures, including total PEEP, and elastance. PaO2/FIO2 was slightly reduced by He/O2 (225±83 vs. 245±82) without significant V̇A/Q̇ change. Conclusions: He/O2 and PEEPe comparably reduced PEEPi and trapped gas volume. However, He/O2 decreased airway resistance and intrathoracic pressures, at a small cost in arterial oxygenation. He/O2 could offer an attractive option in COPD patients with PEEPi/dynamic hyperinflatio

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Occupational Rhinoconjunctivitis and Asthma Caused by Chicory and Oral Allergy Syndrome Associated With Bet v 1-Related Protein

We report the case of a patient working in a factory producing inulin from chicory who developed rhinoconjunctivitis and asthma to the dust of dry chicory roots and oral allergy syndrome to raw fruits and vegetables. Nonspecific bronchial hyperresponsiveness was diagnosed. A provocation test with dry chicory induced acute rhinoconjunctivitis and an immediate asthmatic response with no further clinical symptoms. Skin prick test results were positive to birch pollen and fresh/dry chicory, and negative for inulin. Specific immunoglobulin (Ig) E was >100 kU(A)/L for rBet v 1. Specific IgE were detected by immunoblotting chicory extract with the patient's serum, but not with a control serum. The Main immunoreactive band corresponded to a protein with a molecular weight of approximately 17 kDa, like Bet v 1, and this immunoreactivity was effectively inhibited by preincubating serum with purified Bet v 1. This case documents occupational rhinoconjunctivitis and asthma due to IgE sensitization to inhaled chicory allergens, including one identified for the first time as a 17-kD Bet v 1 homologous protein, with secondary oral allergy syndrome to related foods

Plasmatic ions influence the oxyhemoglobin dissociation curve of patients with chronic obstructive lung disease

Chronic hypoxemia, carboxyhemoglobin and ionic disorders as induced by drug intake may a priori influence the oxyhemoglobin dissociation curve (ODC) of patients suffering from chronic obstructive lung disease (COLD). We have traced the ODC and related indices on whole blood of 54 normal non smoking subjects and of 54 ambulatory smokers or ex-smokers COLD patients whose the FEV(1) was 1.17 +/- 0.45 litres (mean and SD) and the resting PaO2 63.3 +/- 7.7 Torr. In COLD patients HbCO induces a le shift of the ODC according to the following equation : P-50 (Torr) = 27.6 - 0.4 (HbCO - 1) where P-50 is the PO2 necessary to saturate hemoglobin at 50 %. When normalized for HbCO level of 1 % there was no difference in the ODC of the two groups. In contrast, the dispersion around the mean was significantly more important in patients than in control subjects from 20 to 90 % SO2. We attributed this fact to ionic disorders that were present in 51 out of the 54 patients and were presumably due to drug intake. The P-50 (Torr) = -35.55 + 0.325 (Na+) + 0.096(Cl-) + 0.27 (total CO2), r = 0.73, where Na +, Cl- and total CO2 were expressed in mEq/l. We concluded that : 1) hypoxemia was not deep enough in our patients to shift their ODC to the right; 2) plasmatic ions influenced their ODC; 3) and when possible, it is important to correct ionic disorders either by a curative or a preventive approach