Immune response to pertussis vaccine in COPD patients.

Exacerbation triggered by respiratory infection is an important cause of morbidity and mortality in chronic obstructive pulmonary disease (COPD) patients. Strategies aiming to preventing infection may have significant public health impact. Our previous study demonstrated decreased immunological response to seasonal flu vaccination in COPD patients, questioning the efficiency of other vaccines in this group of patients. We performed a prospective, monocenter, longitudinal study that evaluated the humoral and cellular responses upon pertussis vaccination. We included 13 patients with stable COPD and 8 healthy volunteers. No difference in circulating B and T cell subsets at baseline was noted. Both groups presented similar levels of TFH, plasmablasts and pertussis specific antibodies induction after vaccination. Moreover, monitoring T cell immunity after ex-vivo peptide stimulation revealed equivalent induction of functional and specific CD4+ T cells (IFNγ, TNFα and IL-2-expressing T cells) in both groups. Our results highlight the immunological efficiency of pertussis vaccination in this particularly vulnerable population and challenge the concept that COPD patients are less responsive to all immunization strategies. Healthcare providers should stress the necessity of decennial Tdap booster vaccination in COPD patients.

[Therapeutic adherence among asthma patients: Variations according to age groups. How can it be improved? The potential contributions of new technologies]. / Observance thérapeutique dans l'asthme : variation selon les classes d'âge. Comment l'améliorer ? Apport des nouvelles technologies.

While asthma patients' treatment adherence (TA) generally leaves to be desired, few data exist on TA evolution from age group to another. During the meeting of a working group of pneumo-pediatricians and adult pulmonologists, we reviewed the literature on adherence according to age group, examined explanations for poor adherence, and explored ways of improving adherence via new technologies. Asthma is a chronic disease for which TA is particularly low, especially during adolescence, but also among adults. Inhaled medications are the least effectively taken. Several explanations have been put forward: cost and complexity of treatments, difficulties using inhalation devices, poor understanding of their benefits, erroneous beliefs and underestimation of the severity of a fluctuating disease, fear of side effects, neglect, and denial (especially among teenagers). Poor TA is associated with risks of needless treatment escalation, aggravated asthma with frequent exacerbations, increased school absenteeism, degraded quality of life, and excessive mortality. Better compliance is based on satisfactory relationships between caregivers and asthmatics, improved caregiver training, and more efficient transmission to patients of relevant information. The recent evolution of innovative digital technologies opens the way for enhanced communication, via networks and dedicated applications, and thanks to connected inhalation devices, forgetfulness can be limited. Clinical research will also help to ameliorate TA. Lastly, it bears mentioning that analysis of the existing literature is hampered by differences in terms of working definitions and means of TA measurement.

[Guide for management of patients with possible respiratory sequelae after a SARS-CoV-2 pneumonia. Support proposals developed by the French-speaking Respiratory Medicine Society. Version of 10 November 2020]. / Guide de prise en charge des séquelles respiratoires post infection à SARS-CoV-2. Propositions de prise en charge élaborées par la Société de Pneumologie de Langue Française. Version du 10 novembre 2020.

The French-speaking Respiratory Medicine Society (SPLF) proposes a guide for the management of possible respiratory sequelae in patients who have presented with SARS-CoV-2 pneumonia (COVID-19). The proposals are based on known data from previous epidemics, preliminary published data on post COVID-19 follow-up and on expert opinion. The proposals were developed by a group of experts and then submitted, using the Delphi method, to a panel of 22 pulmonologists. Seventeen proposals were validated ranging from additional examinations after the minimum assessment proposed in the SPLF monitoring guide, to inhaled or systemic corticosteroid therapy and antifibrotic agents. These proposals may evolve over time as knowledge accumulates. This guide emphasizes the importance of multidisciplinary discussion.

[Guide for follow-up of patients with SARS-CoV-2 pneumonia. Management proposals developed by the French-language Respiratory Medicine Society. Version of 10 May 2020]. / Guide pour le suivi respiratoire des patients ayant présenté une pneumonie à SARS-CoV-2. Propositions de prise en charge élaborées par la Société de pneumologie de langue française. Version du 10 mai 2020.

The French-language Respiratory Medicine Society (SPLF) proposes a guide for the follow-up of patients who have presented with SARS-CoV-2 pneumonia. The proposals are based on known data from previous epidemics, on acute lesions observed in SARS-CoV-2 patients and on expert opinion. This guide proposes a follow-up based on three categories of patients: (1) patients managed outside hospital for possible or proven SARS-CoV-2 infection, referred by their physician for persistent dyspnoea; (2) patients hospitalized for SARS-CoV-2 pneumonia in a medical unit; (3) patients hospitalized for SARS-CoV-2 pneumonia in an intensive care unit. The subsequent follow-up will have to be adapted to the initial assessment. This guide emphasises the possibility of others causes of dyspnoea (cardiac, thromboembolic, hyperventilation syndrome…). These proposals may evolve over time as more knowledge becomes available.

[How to reduce lung cancer mortality among people living with HIV?] / Comment réduire la mortalité par cancer du poumon chez les personnes vivant avec le VIH ? Du sevrage tabagique au dépistage radiologique.

Lung cancer is the leading cause of cancer related death among people living with HIV (PLHIV). Tobacco exposure is higher among PLHIV (38.5%) and mainly explains the increased risk of lung cancer. To reduce lung cancer mortality, two approaches need to be implemented: lung cancer screening with low-dose thoracic CT scan and smoking cessation. Low dose CT scan is feasible in PLHIV. The false positive rate is not higher than in the general population, except for cases with CD4 <200/mm3. The impact on survival remains to be assessed. Despite the high prevalence, smoking cessation research among PLHIV is scarce. Very low quality data from 11 studies showed that more intensive smoking cessation interventions were effective in achieving short-term abstinence. A single randomized phase 3 trial showed the superiority of varenicline compared to placebo in long-term smoking cessation. The maximum benefit of reducing lung cancer mortality should be obtained by combining smoking cessation and lung cancer screening.

Study protocol for a pragmatic randomised controlled trial evaluating efficacy of a smoking cessation e-'Tabac Info Service': ee-TIS trial.

INTRODUCTION: A French national smoking cessation service, Tabac Info Service, has been developed to provide an adapted quitline and a web and mobile application involving personalised contacts (eg, questionnaires, advice, activities, messages) to support smoking cessation. This paper presents the study protocol of the evaluation of the application (e-intervention Tabac Info Service (e-TIS)). The primary objective is to assess the efficacy of e-TIS. The secondary objectives are to (1) describe efficacy variations with regard to users' characteristics, (2) analyse mechanisms and contextual conditions of e-TIS efficacy. METHODS AND ANALYSES: The study design is a two-arm pragmatic randomised controlled trial including a process evaluation with at least 3000 participants randomised to the intervention or to the control arm (current practices). Inclusion criteria are: aged 18 years or over, current smoker, having completed the online consent forms, possessing a mobile phone with android or apple systems and using mobile applications, wanting to stop smoking sooner or later. The primary outcome is the point prevalence abstinence of 7 days at 6 months later. Data will be analysed in intention to treat (primary) and per protocol analyses. A logistic regression will be carried out to estimate an OR (95% CI) for efficacy. A multivariate multilevel analysis will explore the influence on results of patients' characteristics (sex, age, education and socioprofessional levels, dependency, motivation, quit experiences) and contextual factors, conditions of use, behaviour change techniques. ETHICS AND DISSEMINATION: The study protocol was reviewed by the ethical and deontological institutional review board of the French Institute for Public Health Surveillance on 18 April 2016. The findings of this study will allow us to characterise the efficacy of e-TIS and conditions of its efficacy. These findings will be disseminated through peer-reviewed articles. TRIAL REGISTRATION NUMBER: NCT02841683; Pre-results.

Platelets are dispensable for antibody-mediated transfusion-related acute lung injury in the mouse.

UNLABELLED: Essentials Role of platelets in immunological transfusion-related acute lung injury (TRALI) is debated. Immunological TRALI was tested in mice exhibiting severe thrombocytopenia or platelet dysfunction. Platelets are required to prevent lung hemorrhage but not edema formation and respiratory distress. Platelets are dispensable for the initiation and development of TRALI. SUMMARY: Background Transfusion-related acute lung injury (TRALI) is a serious transfusion-related complication. Previous conflicting studies have indicated that platelets are either crucial or dispensable for TRALI. Objectives To evaluate the role of platelets in major histocompatibility complex (MHC) I-induced-TRALI. Methods Antibody-mediated TRALI was experimentally induced in mice by lipopolysaccharide priming followed by the administration of an anti-MHC I mAb. Results TRALI was tested in the context of severe thrombocytopenia provoked by the administration of diphtheria toxin (DT) in transgenic iDTR mice selectively expressing DT receptor in megakaryocytes. The pathologic responses occurring within the first 10 min following the injection of the anti-MHC I mAb, i.e. the severity of lung edema and the drop in aortic blood oxygenation, were similar in severely thrombocytopenic DT-iDTR and control mice. At later times, mortality was nevertheless increased in DT-iDTR mice, owing to lung hemorrhages. When less severe thrombocytopenia was induced with an antiplatelet mAb, TRALI started and developed similarly as in control mice, but hemorrhages were absent. Furthermore, when platelet functions were defective because of administration of aspirin or clopidogrel, or because of glycoprotein (GP)IIbIIIa deficiency, TRALI still developed but no lung hemorrhages were observed. In contrast, when GPVI was immunodepleted, TRALI still occurred, but was occasionally accompanied by hemorrhages. Conclusions Platelets are dispensable for the initiation and development of MHC I-induced TRALI. Although they do not protect against the disruption of the vascular endothelial cell barrier and the subsequent plasma leakage and edema formation, platelets are essential to prevent more serious damage resulting in hemorrhages in alveoli.

Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.

Inhaled nitric oxide for acute chest syndrome in adult sickle cell patients: a randomized controlled study.

PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. CLINICAL TRIAL REGISTRATION: NCT00748423.

ER stress induces NLRP3 inflammasome activation and hepatocyte death.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1α and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1ß secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1ß secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

Stevens-Johnson syndrome and toxic epidermal necrolysis: follow-up of pulmonary function after remission.

BACKGROUND: Acute-stage specific bronchial epithelial detachment has been described in 27% of patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To assess the pulmonary function of patients with SJS/TEN after remission. METHODS: Analysis of pulmonary function tests (PFTs) performed during the usual follow-up of patients with SJS/TEN managed in a referral centre from April 2007 to January 2010. RESULTS: Of 58 patients admitted, 32 underwent PFTs (17 male, 15 female). The median time from the acute stage to PFTs was 3 months (interquartile range 1-18). Three patients had grade 2 dyspnoea. Eighteen patients (56%) had abnormal PFTs, including 13 patients (41%) with moderately altered diffusion capacity for carbon monoxide (DLCO ) normalized by the alveolar volume (VA) (giving the ratio KCO , which equals DLCO /VA) and five patients with decreased total lung capacity. No airway obstruction was observed. Patients with decreased KCO had higher initial detached body surface area than others (30% vs. 10%, P = 0·006), as did those with decreased DLCO (25% vs. 10%; P = 0·054). There were correlations between detached body surface area and both KCO (r = -0·41, P = 0·026) and DLCO (r = -0·47, P = 0·011). Among 10 patients with decreased KCO on the first PFT, eight patients had a sustained decrease in KCO on a second PFT. CONCLUSIONS: More than half of patients with SJS/TEN displayed abnormalities on PFTs, mainly diffusion impairment, which was associated with higher initial skin surface detachment. These abnormalities were mostly asymptomatic and remained stable over time.

Diagnosis of alpha-1 antitrypsin deficiency: modalities, indications and diagnosis strategy.

Alpha-1 antitrypsin (α1-AT) deficiency is an autosomal recessive genetic disorder, which predisposes affected patients to development of pulmonary emphysema or liver cirrhosis. Despite the guidelines from the American Thoracic Society and the European Respiratory Society about α1-AT deficiency screening, it remains significantly under recognized. So, it seems necessary to propose an efficient and suitable biological approach to improve diagnosis and management of α1-AT deficiency. α1-AT is a 52 kDa glycoprotein predominantly produced in the liver and its physiological serum concentration for adults ranges from 0.9 to 2.0g/L (17-39 µmol/L). It is encoded by the SERPINA1 gene, which is highly pleomorphic, and to date, more than 100 alleles have been identified. α1-AT testing would initially involve quantification of serum α1-AT concentration with possible complementary measurement of the elastase inhibitory capacity of serum. If the serum α1-AT concentration is reduced below the reference value, two strategies for laboratory testing can be used: (i) serum α1-AT phenotyping by isoelectric focusing which allows identification of the most common variant designated as the PI M variant but also of various deficient variants besides the predominant PI S and PI Z ones; (ii) genotyping by allele-specific PCR methods which allows only identification of the deficient PI S and PI Z alleles. Identification of the null alleles or of other rare deficient alleles can be performed by direct sequencing of the whole SERPINA1 gene as a reflex test.

Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice.

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn(-/-) mice compared with wild-type (Wt) mice after I-R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn(-/-) mice versus Wt mice after I-R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn(-/-) mice versus Wt mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.