[The place of bronchoalveolar lavage in the diagnosis of pneumonia in the immunocompromised patient]. / Place du lavage broncho-alvéolaire dans l'exploration d'une pneumopathie de l'immunodéprimé.

INTRODUCTION: Bronchoalveolar lavage (BAL) was previously considered as the standard diagnostic procedure to investigate pneumonia occurring in immunocompromised patients, and it is probably still widely used. However, the development of new microbiological diagnostic tools, applicable to samples obtained non-invasively, leads to questioning of the predominant place of BAL in this situation. BACKGROUND: The available studies agree on the acceptable tolerance of BAL performed in immunocompromised patients. Although imperfect, the diagnostic yield of BAL in immunocompromised patients is well established, but it may vary between studies depending on the underlying disease. However, it must also be compared to the yield of non-invasive microbiological tools, now widely available and effective. The position of BAL remains important both for the diagnosis of fungal infections (invasive aspergillosis, pneumocystis pneumonia) and non-infectious lung diseases both of which occur frequently in immunocompromised patients. CONCLUSION: The place of BAL in the diagnostic work-up of pneumonia occurring in immunocompromised patients must be considered in the framework of a structured consideration, taking into account the diagnostic performance of non invasive microbiological tests and the broad spectrum of lung diseases occurring in this context.

[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.

Bacillus Calmette-Guerin infection following intravesical instillation: Does the strain matter?

PURPOSE: Intravesical BCG is the standard treatment of non-muscle invasive bladder cancer. No difference has yet been reported in the safety profiles of the various BCG strains. METHODS: A nationwide multidisciplinary retrospective survey was conducted between January 2013 and December 2016 to identify cases of BCG infection and differentiate them based on the type of BCG strain used. RESULTS: Forty patients were identified (BCG RIVM 28; other strains 8; unknown 4). Patients treated with BCG RIVM were less severely ill, with fewer occurrences of septic shock (3.6% vs. 50%, P=0.003) and ICU admission (7.1% vs. 62.5%, P=0.003). A higher frequency of pulmonary miliaries (71.4% vs. 12.5%, P=0.005) but lower transaminase levels (mean AST 65 vs. 264 U/L, P=0.001) were observed in these patients. No difference in terms of recovery was reported. CONCLUSION: The type of BCG strain could correlate with the frequency and severity of subsequent BCG infections.

[BCG infection following intravesicular immunotherapy for bladder cancer]. / BCGites après immunothérapie pour cancer de vessie, une pathologie hétérogène: physiopathologie, description clinique, prise en charge diagnostique et thérapeutique.

BACKGROUND: Bacille of Calmette et Guérin (BCG) immunotherapy is the most effective treatment for non-muscle-invasive bladder cancer. Yet, potentially severe localized or systemic mycobacterial infections can happen. STATE OF KNOWLEDGE: In a patient who underwent BCG instillation for bladder cancer, the diagnosis of BCG infection is usually suggested by more than 3 days of high-grade fever and systemic and/or local symptoms with no other plausible alternative diagnosis. BCG infection can be localized (usually to the genitourinary tract, the bones or blood vessels) or systemic (mainly with pulmonary and hepatic involvements). The presence of granuloma in tissue biopsies (other than from the genitourinary tract) supports the diagnosis. The advent of polymerase chain reaction has recently improved the sensitivity of microbiological investigations. The management of BCG infection is not well established but relies on broad-spectrum antimycobacterial therapy (with the exclusion of pyrazinamide), glucocorticoids (in the context of general symptoms refractory to antimicrobial therapy alone) and occasionally surgery. CONCLUSION: BCG infection is a rare but not exceptional complication of BCG immunotherapy with heterogeneous clinical presentation. Prospective studies are warranted in order to improve treatment outcomes.

Differential blockade by nifedipine and omega-conotoxin GVIA of alpha 1- and beta 1-adrenoceptor-controlled calcium channels on motor nerve terminals of the rat.

Electrically evoked release of [3H]acetylcholine ([3H]ACh) from the rat phrenic nerve and its facilitation by stimulation of presynaptic alpha 1- and beta 1-adrenoceptors were investigated in the absence and presence of nifedipine and omega-conotoxin GVIA. Both calcium channel antagonists did not modify electrically evoked [3H]ACh release, but selectively blocked the effect triggered by both facilitatory adrenergic receptors. The increase in [3H]ACh release mediated via beta 1-adrenoceptor activation was abolished by low concentrations (1 nM) of omega-conotoxin GVIA, whereas nifedipine (100 nM) abolished the facilitatory effect mediated via alpha 1-adrenoceptor stimulation. Therefore, the beta 1-adrenoceptor is apparently coupled to a calcium channel that can be regarded as of the N-type, and the alpha 1-adrenoceptor is apparently coupled to a calcium channel that appears as a subtype of the L-type which is not sensitive to omega-conotoxin GVIA.

Differential effects of calcium channel antagonists (omega-conotoxin GVIA, nifedipine, verapamil) on the electrically-evoked release of [3H]acetylcholine from the myenteric plexus, phrenic nerve and neocortex of rats.

Electrically-evoked release of [3H]acetylcholine from autonomic neurons (myenteric plexus), motoneurons (phrenic nerve) and the central nervous system (neocortex) was investigated in the presence and absence of the calcium channel antagonists omega-conotoxin GVIA, nifedipine and verapamil, whereby the same species (rat) was used in all experiments. Release of [3H]acetylcholine was measured after incubation of the tissue with [3H]choline. omega-Conotoxin GVIA markedly reduced (70%) the evoked release of [3H]acetylcholine from the myenteric plexus of the small intestine (IC50: 0.7 nmol/l) with a similar potency at 3 and 10 Hz stimulation. An increase in the extracellular calcium concentration attenuated the inhibitory effect of omega-conotoxin GVIA. Release of [3H]acetylcholine from the rat neocortex was also inhibited (90%) by omega-conotoxin GVIA, but the potency was 19-fold lower (IC50: 13 nmol/l). However, the release of [3H]acetylcholine from the phrenic nerve was not reduced by omega-conotoxin GVIA (100 nmol/l) at 1.8 mmol/l calcium (normal concentration), whereas omega-conotoxin GVIA inhibited evoked [3H]acetylcholine release by 47% at 0.9 mmol/l calcium. Neither nifedipine (0.1 and 1 mumol/l) nor verapamil (0.1, 1 and 10 mumol/l) modified the evoked release of [3H]acetylcholine from the myenteric plexus and the phrenic nerve. Acetylcholine release from different neurons appears to be regulated by different types of calcium channels. N-type channels play the dominant role in regulating acetylcholine release from both the myenteric plexus and the neocortex, whereas acetylcholine release from motor nerves is regulated by calcium channel(s) not yet characterized.

[Value of several examination systems in patients with carpal tunnel syndrome. Comparison of Dellon computer-assisted sensation test with Mellesi hand status and Levine examination scheme]. / Wertigkeit verschiedener Untersuchungssysteme bei Patienten mit Karpaltunnelsyndrom. Vergleich des computerunterstützten Sensibilitätstestes nach Dellon mit dem Handstatus nach Millesi und dem Untersuchungsschema nach Levine.

The goal of the presented carpal tunnel syndrome (CTS) follow-up study was to compare the clinical value of the Millesi hand function score with the "Pressure Specifying Sensory Device" (PSSD) introduced by A. L. Dellon using self-administered patient questionnaires. 25 patients (10 male, 15 female) with an electrodiagnostically confirmed CTS were enrolled in this study, performing one preoperative and five postoperative examinations over 24 weeks. 12 of the 25 patients underwent an "open" two-portal carpal tunnel release with two minimal incisions (group OT); the other 13 patients were treated with a two-portal endoscopic carpal tunnel release (group ET). Additionally, in eleven out of the twelve patients of group OT, an epineuriotomy of the median nerve was performed during the same session. Concerning preoperative data of the Millesi score and the PSSD, no statistically significant differences were found between group OT and ET. However, preoperative comparison with the contralateral hand demonstrated a reduction in hand function of 15% and an increase in the pressure perception threshold of 41% compared to normative data could be measured with the PSSD. The subjective functional value of the hand was objectively evacuated using the Levine score. In the second postoperative week, a significant decrease in hand function could be obtained with the Millesi score in group OT. In group ET, the decrease in hand function representing the operative trauma was significantly lower than in group OT. Data of the static one- and two-point pressure perception threshold revealed a statistically significant improvement of the sensibility in both groups. The results of the Millesi score recorded at the last examination in the 24th postoperative week showed an improvement in hand function in both groups compared to preoperative data. Concerning static one- and two-point measurements with the PSSD, distinct improvements compared to the preoperative data could also be detected in both groups although significant differences between group OT and ET were evident: Data of group OT regarding the whole postoperative course demonstrate a continuous improvement in sensibility of the index finger. In contrast, the analysis of the PSSD measurements in group ET revealed an increase in all the parameters starting in the sixth postoperative week and ending with significantly worse static one- and two-point threshold measurements than in group OT. On the other hand, data of self-administered patient questionnaires using the Levine Score revealed significant improvements in hand function and reduction in pain intensity in both groups compared to preoperative results. Differences between both groups at the end of the examination course were not evident. In conclusion, the Millesi hand score with its emphasis on the motor function proved to be a reliable method to record the severity of CTS preoperatively, the severity of the surgical trauma and changes in the course of rehabilitation of the affected hand. A good correlation was found between data obtained with the Millesi Score and the self-administered patient questionnaires according to Levine. But when compared with the PSSD, both methods could not directly document the preoperative status and postoperative changes of the median nerve. Preoperative static two-point pressure threshold measurements with the PSSD confirmed their status as a screening parameter as published by A. L. Dellon. In the postoperative course of group ET, a distinct worsening in the sensibility of the index and little finger could only be detected with the PSSD before the patients noticed the onset of related symptoms.

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8.

The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a large-spectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress.

In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2α phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca(2+)-ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.

Immunogenic death of colon cancer cells treated with oxaliplatin.

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.