Impact of COVID-19 on posttraumatic stress disorder in ICU survivors: a prospective observational comparative cohort study.

BACKGROUND: Posttraumatic stress disorder (PTSD) after a stay in the intensive care unit (ICU) can affect one in five ICU survivors. At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, admission to the ICU for COVID-19 was stressful due to the severity of this disease. This study assessed whether admission to the ICU for COVID-19 was associated with a higher prevalence of PTSD compared with other causes of ICU admission after adjustment for pre-ICU psychological factors. METHODS: This prospective observational comparative cohort study included 31 ICUs. Eligible patients were adult ICU survivors hospitalized during the first wave of COVID-19 pandemic in France, regardless of the reason for admission. The prevalence of presumptive diagnosis of PTSD at 6 months was assessed using the PTSD Checklist for DSM-5 (PCL-5). Sociodemographics, clinical data, history of childhood trauma (Childhood Trauma Questionnaire [CTQ]), and exposure to potentially traumatic events (Life Events Checklist for DSM-5 [LEC-5]) were assessed. RESULTS: Of the 778 ICU survivors included during the first wave of COVID-19 pandemic in France, 417 and 361 were assigned to the COVID-19 and non-COVID-19 cohorts, respectively. Fourteen (4.9%) and 11 (4.9%), respectively, presented with presumptive diagnosis of PTSD at 6 months (p = 0.976). After adjusting for age, sex, severity score at admission, use of invasive mechanical ventilation, ICU duration, CTQ and LEC-5, COVID-19 status was not associated with presumptive diagnosis of PTSD using the PCL-5. Only female sex was associated with presumptive diagnosis of PTSD. However, COVID-19 patients reported significantly more intrusion and avoidance symptoms than non-COVID patients (39% vs. 29%, p = 0.015 and 27% vs. 19%, p = 0.030), respectively. The median PCL-5 score was higher in the COVID-19 than non-COVID-19 cohort (9 [3, 20] vs. 4 [2, 16], p = 0.034). CONCLUSION: Admission to the ICU for COVID-19 was not associated with a higher prevalence of PTSD compared with admission for another cause during the first wave of the COVID-19 pandemic in France. However, intrusion and avoidance symptoms were more frequent in COVID-19 patients than in non-COVID-19 patients. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03991611, registered on June 19, 2019.

Chronic Spontaneous Urticaria in Belgium: Deciphering the Clinical Profile and Treatment of Patients Visiting an Urban City Immunology Department.

BACKGROUND: Chronic urticaria (CSU) is a chronic inflammatory mast cell-driven disorder of which reliable clinical data in Belgium are lacking. This study focusses on clinical characteristics of CSU patients presenting at an urban Immunology-Allergology department. METHODS: Outpatients with CSU were included from 2018 to 2021. Clinical characteristics, Dermatology Life Quality Index (DLQI) and Urticaria activity score (UAS7) were collected by thorough anamnesis and questionnaires. Furthermore, patients underwent provocational testing, an autologous serum skin test (ASST) and a blood analysis. RESULTS: The study included 49 CSU patients and 20 non-CSU subjects. CSU was distributed differently with age and sex, showing higher numbers in female patients below the age of 46 years. 67% of CSU patients had accompanying angioedema of which 9% were reported genital. CSU patients scored a mean 8/30 on their DLQI questionnaire. There was no significant difference in immunoglobulin E (IgE), C-reactive protein, and tryptase levels between CSU patients and controls. Oral glucocorticosteroids were prescribed in 23% of CSU patients during their disease course though only half of these patients had a severity grade 4 CSU. In 82% of the included CSU patients, Urticaria Control Test (UCT) scores were below 12. When we hypothetically considered low IgE levels and high IgG anti-thyroid peroxidase levels as differentiation marker for autoimmune (ai)CSU and non-aiCSU, we found that 4% of all included CSU patients could be considered aiCSU. CONCLUSION: Generally, the inner-city population displayed the same clinical characteristics, as previous cohorts from Northern Europe. The relatively high rate of CSU patients receiving oral glucocorticosteroid treatment for their disease though not always classified as severe, underlines the need to train doctors of various specialties in the treatment algorithms of CSU. Furthermore, by looking at potential autoimmune characteristics, our findings open perspectives on the identification of new routinely used clinical parameters for the detection of aiCSU, a relatively small immunological subtype of CSU.

An unequal endotoxin distribution in typical house types of Ho Chi Minh city.

BACKGROUND: Endotoxin exposure may cause asthma exacerbations and contribute to non-atopic respiratory diseases. Viet Nam, a country with multiple house types, is lacking data on indoor contamination by endotoxin in regard with house types. OBJECTIVE: The comparison of measured settled dust endotoxin levels among house types in Ho Chi Minh city will allow to classify the house types regarding health risks. METHODS: This study is a cross-sectional study. Five identified house types were selected: apartment (APA), rental (REN), rural (RUR), slum (SLU) and tube house (TUB). One hundred house's endotoxin contamination was evaluated by questionnaire and dust sampling. Endotoxin concentration was measured by kinetic chromogenic Limulus assay. RESULTS: dotoxin concentration (geometric mean 126.0 EU/mg, 95%CI 118.3-133.7) is particularly high in settled house dust compared to western countries and is significantly associated with the house type. The highest level was found in RUR in each room (p = 0.002 for living room; p < 0.0001 for bedrooms and for kitchens). Concerning levels in the different rooms, APA and TUB form a low group while REN and SLU (p < 0.001) form a median group and RUR the highest (p < 0.001). Differences in endotoxin levels were associated to the presence of dog, chicken and farm animals, wood cooking, air-conditioning usage. CONCLUSIONS: Further understanding of the relevant factors to endotoxin levels would contribute to prevent asthma exacerbations and chronic respiratory diseases. Public health interventions to reduce exposure to endotoxin include improving housing conditions, eliminating risk factors and a priority to high-risk house types.

Markers for the involvement of endothelial cells and the coagulation system in chronic urticaria: A systematic review.

Chronic urticaria (CU) is a chronic inflammatory mast cell-driven disorder. Endothelial cells (ECs) contribute importantly to key features of CU. Several markers of EC (dys)function in CU have been reported, but have not yet been systematically reviewed. In this study, we systematically reviewed and categorized all published markers of EC functions in CU through a comprehensive search in Pubmed, The Cochrane Library, Web of Science, and SCOPUS using the following Mesh terms: CU AND pathogenesis AND (vasculopathy OR microangiopathy OR ECs OR marker). In total, 79 articles were selected and the identified biomarkers were categorized according to EC (dys)function in CU. The most frequent and consistently reported upregulated biomarkers in CU skin were adhesion molecules, TF, and P-selectin. The most frequently reported upregulated and reliable biomarkers in sera of CU patients were F1+2 for coagulation cascade involvement, D-dimers for fibrinolysis, and MMP-9 for vascular permeability. Emerging biomarkers described in the selected articles were endostatin, heat shock proteins, cleaved high molecular weight kininogen, and adipokines. This systematic review contributes to the pool of growing evidence for vascular involvement in CU where EC dysfunction is present in different aspects of cell survival, maintenance of vascular structure, and coagulation/fibrinolysis balance.

Molecular monitoring of therapeutic milestones and clinical outcomes in patients with chronic myeloid leukemia.

BACKGROUND: In the current study, the authors determined whether adhering to molecular monitoring guidelines in patients with chronic myeloid leukemia (CML) is associated with major molecular response (MMR) and assessed barriers to adherent monitoring. METHODS: Newly treated patients with CML from the Quebec province-wide CML registry from 2005 to 2016 were included. Timely polymerase chain reaction (tPCR) was defined as the molecular assessment of BCR-ABL1 at the 3-month, 12-month, and 18-month time points from the initiation of tyrosine kinase inhibitor (TKI) therapy. The cohort was analyzed as a nested case-control study. Cases with a first-ever MMR (BCR-ABL1 ≤0.1%, assessed at any time during follow-up) were matched to up to 5 controls by duration of TKI therapy, volume of patients with CML at the treatment center, year of cohort entry, and age. Odds ratios (ORs) for the performance of tPCR and MMR were adjusted for sex, comorbidities, type of TKI, and other important covariates. RESULTS: The cohort included 496 patients. Of 392 MMR events, 67.9% occurred before 18 months. The performance of tPCR was associated with a doubling of the MMR rate (OR, 2.23; 95% confidence interval [95% CI], 1.56-3.21) and was similar with 1 to 3 tPCRs performed (P = .67). Furthermore, tPCRs at 3 months (OR, 2.77; 95% CI, 1.81-4.23) and 12 months (OR, 3.00; 95% CI, 1.64-5.49) were associated with achieving early MMR, whereas tPCRs at 18 months were not (OR, 1.23; 95% CI, 0.80-1.89). Low-volume centers were found to have lower adherence to tPCR (OR, 0.60; 95% CI, 0.40-0.89). CONCLUSIONS: Timely molecular assessment at 3 months and 12 months appears to benefit patients with CML. Adherence to timely monitoring should be encouraged, especially in low-volume treatment centers.

Relationship between mold exposure, specific IgE sensitization, and clinical asthma: A case-control study.

BACKGROUND: Most of the findings related to the noxious effect of mold sensitization on asthma come from investigations based on Alternaria alternata, Cladosporium herbarum, and Aspergillus fumigatus. However, species such as Penicillium spp, Cladosporium sphaerospermum, Cladosporium cladosporioides, or Aspergillus versicolor display a more pronounced indoor tropism, and their potential harmful respiratory effects cannot be neglected. OBJECTIVE: The goal of this work was to relate mold sensitizations with asthma severity and with the level of indoor mold contamination among mold-sensitized patients with asthma and nonsensitized patients with asthma. METHODS: A case-control study was conducted and several asthma severity markers were compared between patients with asthma with and without mold sensitization. Indoor contamination of patients' dwellings was also investigated. RESULTS: Our findings confirmed the association between sensitization to A fumigatus and severity for patients with asthma in contrast with sensitization to other species. Indoor mold contamination was detected in approximately 90% of dwellings. Overall mold exposure was not associated with asthma severity. However, regardless of the sensitization, exposure to A fumigatus and Penicillium spp in dust was linked to an increased risk of severe asthma. CONCLUSION: The harmful nature of mold sensitization and mold exposure for patients with asthma was not confirmed in this study. However, sensitization to A fumigatus was associated with an increased risk for severe asthma. A better investigation of the properties of Penicillium spp is recommended because its exposure was found to be associated with a more pronounced impairment of lung function.

Development of a Dot-Blot Assay for the Detection of Mould-Specific IgE in the Belgian Population.

BACKGROUND: Data on mould sensitization in the general population are scarce and mostly on Aspergillus fumigatus, Alternaria alternata and Cladosporium herbarum. OBJECTIVES: To validate a dot-blot assay for the detection of specific IgE and evaluate the prevalence of mould sensitization in a healthy population. METHODS: The dot-blot assay was validated against the CAP test. Sensitization rate to ten common indoor and outdoor mould species in 344 serum samples was calculated. For each serum with more than one reactivity, the "major sensitization" defined as the strongest response against a single mould species was calculated. RESULTS: Intra- and inter-assay variations were both below 20%, and the positivity threshold of the test was of 0.418 kU/L for A. fumigatus. Correlation with CAP results was strong. The overall prevalence of sensitization was 32.8%, and the commonest sensitizations were against A. alternaria, A. flavus and A. niger (around 15%). The most frequent "major reactivities" were against A. niger and A. alternata (20-30%). In 25.1% of the samples, "major reactivities" were directed against a group of moulds commonly found indoor (Penicillium spp., Aspergillus versicolor, Cladosporium sphaerospermum and Cladosporium cladosporioides). CONCLUSIONS: The dot-blot assay was validated for the detection of mould-specific IgE. In the general population, sensitization to indoor species was common and accounted for 25% of overall mould sensitizations.

Inflammation induced by inhaled lipopolysaccharide depends on particle size in healthy volunteers.

AIMS: In drug development, the anti-inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size. METHODS: Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 µm), MB2 (3.2 µm) and Pari (7.9 µm)]. Participants inhaled three boluses of a 20 µg (technetium 99 m-labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma-scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges. RESULTS: MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel-1 , respectively, vs. 67.9 (±20.6) counts pixel-1 ; P < 0.01]. MB2 and Pari caused higher levels of blood C-reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C-reactive protein levels correlated positively with lung deposition (P < 0.01). CONCLUSIONS: Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.

Chronic spontaneous urticaria: Evidence of systemic microcirculatory changes.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin disease where activation of endothelial cells (ECs) at sites of skin lesions leads to increased blood flow, leakage of fluid into the skin, cellular infiltration, and vascular remodeling. To understand the disease duration and the sometimes vague systemic symptoms accompanying flares, the objective of this study was to examine if CSU comes with systemic vascular changes at the microcirculatory level. METHODS: We investigated CSU patients (n = 49) and healthy controls (HCs, n = 44) for microcirculatory differences by nailfold videocapillaroscopy (NVC) and for blood levels of the soluble EC biomarkers serum vascular endothelial growth factor (VEGF), soluble E-selectin, and stem cell factor (SCF). Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU). RESULTS: CSU patients had significantly lower capillary density, more capillary malformations, and more irregular capillary dilations than HCs on NVC. Serum levels of VEGF, soluble E selectin and SCF were similar in CSU patients and HCs. CSU patients with higher VEGF levels had significantly more abnormal capillaries. Patients with markers of aiCSU, that is, low IgE levels or increased anti-TPO levels, had significantly more capillaries and less capillary dilations than those without. CONCLUSION: Our results suggest that CSU comes with systemic microcirculatory changes, which may be driven, in part, by VEGF.

Expression of calgranulin A/B heterodimer after acute inhalation of endotoxin: proteomic approach and validation.

BACKGROUND: The acute inhalation of endotoxin mimicks several aspects of the inflammation related to chronic obstructive pulmonary disease (COPD). The aim of the current study was to identify and to validate biomarkers of endotoxin-induced airways' inflammation. METHODS: The cellular count in the induced-sputum, was measured before and after an inhalation of 20 mcg endotoxin, in 8 healthy volunteers. A proteomic analysis was applied to identify the more relevant proteins expression, before measurement by ELISA. The amplitude and the repeatability of the markers were evaluated among another population of 12 healthy subjects. RESULTS: There was a significant rise of viable cells (p <0.01), macrophages (p <0.05), and neutrophils (p <0.02) 24 hours after endotoxin inhalation, and of neutrophils (p <0.02) and lymphocytes (p <0.05) at 6 hours. Among the highest amplitude responses, the two dimensional electrophoretic separation shown proteolytic activity and overexpression of protein spots. By MALDI-TOF mass spectrometry, the last were identified as calgranulin A and B. The expression of the bioactive A/B heterodimeric complex was confirmed by ELISA both in the sputum (p <0.01) and at the blood level (p <0.01). The intra-subject repeatability of the sputum calgranulin A/B was highly significant (p <0.0001). CONCLUSION: In healthy subjects, the inhalation of endotoxin induced expression of sputum calgranulin A/B that could be a biomarker of the endotoxin response/exposure.

A Proposal to Differentiate ACO, Asthma and COPD in Vietnam.

BACKGROUND: In low- and middle-income countries, such as Vietnam, the population is exposed to multiple risks, leading to frequent allergic asthma, COPD and their overlap (ACO). We aimed to differentiate asthma and COPD, so that recommended treatments can be applied. METHODS: We hypothesized that during life, the cumulative exposure to noxious particles increases the relative prevalence of COPD, while due to immuno-senescence, the prevalence of allergic asthma decreases with age. Among 568 patients with chronic respiratory symptoms, five phenotypes were defined, based on responsiveness to a bronchodilator (BD), diffusion capacity and cumulative smoking. Then the relative prevalence of each phenotype was related with age. RESULTS: the smoker BD irreversible patients were considered "COPD", while the full BD responders and non-smoking BD incomplete responders were "asthmatics". The other patients were ACO, distributed as "like-COPD" or "like-asthma", based on decreased or normal diffusion capacity. The relative prevalence of asthma, COPD and ACO were 26, 42 and 32% (18% "like-asthma", 14% "like-COPD"). CONCLUSION: Vietnamese patients with chronic respiratory symptoms were considered as falling into asthma or COPD groups, based on cumulative smoking, spirometry with reversibility and diffusion capacity. The relative prevalence of asthma and COPD were 44 and 56%, respectively, most of which did not require corticosteroids.

Identification of Modifiable Risk Factors of Exacerbations Chronic Respiratory Diseases with Airways Obstruction, in Vietnam.

OBJECTIVES: to determine modifiable risk factors of exacerbations in chronic respiratory diseases with airways obstruction (i.e., asthma and COPD) in southern Vietnam. METHODS: an environmental and health-related behavioural questionnaire was submitted to patients with both chronic respiratory symptoms and airways obstruction. An exacerbation was defined as any acute worsening in clinical symptoms requiring a change in treatment, in a patient receiving prophylactic therapy. RESULTS: 235 patients were evaluated, including 131 (56%) chronic obstructive pulmonary disease (COPD) and 104 (44%) asthmatics. There were 75% males and 69% smokers. Occupational exposure accounted for 66%, mainly among construction and industry workers. Smoking was associated with more severe airways obstruction. Respiratory exacerbations were reported in 56/235 patients (24%). The risk of exacerbation was increased in patients with a lower education level, exposure to occupational pollutants, cumulative smoking ≥ 20 pack year, housing space < 10 m2, and poorly ventilated housing. Based on multivariate analysis, the risk of exacerbation remained significantly higher among patients with occupational exposure and low housing space per person. CONCLUSIONS: besides smoking cessation, more supportive policies, including improvement of occupational environment and housing design for better ventilation, are needed to prevent the severity of chronic respiratory diseases in Vietnam.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

On directed information theory and Granger causality graphs.

Directed information theory deals with communication channels with feedback. When applied to networks, a natural extension based on causal conditioning is needed. We show here that measures built from directed information theory in networks can be used to assess Granger causality graphs of stochastic processes. We show that directed information theory includes measures such as the transfer entropy, and that it is the adequate information theoretic framework needed for neuroscience applications, such as connectivity inference problems.