Tocilizumab-treated convalescent COVID-19 patients retain the cross-neutralization potential against SARS-CoV-2 variants.

Although tocilizumab treatment in severe and critical coronavirus disease 2019 (COVID-19) patients has proven its efficacy at the clinical level, there is little evidence supporting the effect of short-term use of interleukin-6 receptor blocking therapy on the B cell sub-populations and the cross-neutralization of SARS-CoV-2 variants in convalescent COVID-19 patients. We performed immunological profiling of 69 tocilizumab-treated and non-treated convalescent COVID-19 patients in total. We observed that SARS-CoV-2-specific IgG1 titers depended on disease severity but not on tocilizumab treatment. The plasma of both treated and non-treated patients infected with the ancestral variant exhibit strong neutralizing activity against the ancestral virus and the Alpha, Beta, and Delta variants of SARS-CoV-2, whereas the Gamma and Omicron viruses were less sensitive to seroneutralization. Overall, we observed that, despite the clinical benefits of short-term tocilizumab therapy in modifying the cytokine storm associated with COVID-19 infections, there were no modifications in the robustness of B cell and IgG responses to Spike antigens.

Fitness to Serve in the Armed Forces and Internal Medicine: A Retrospective Study.

INTRODUCTION: Assessment of the medical fitness to serve in the armed forces has two objectives: to prevent the military operations from being jeopardized by a medical issue, and to protect soldiers from the sequelae of diseases that could become complicated in the operational field, especially in overseas operations where soldiers are exposed to a remote setting and a long evacuation time. Little is known about fitness decisions for soldiers with systemic or autoimmune diseases. Therefore, we conducted a single-center retrospective study of internal medicine fitness decisions. MATERIALS AND METHODS: All the fitness decisions discussed from September 2019 to December 2020 in our department of internal medicine were reviewed. Gender, age, army or service, rank, garrison and health topic were collected from the medical files. Our Military Hospital local ethics committee, in accordance with the French law, approved this study. RESULTS: There were 41 cases, involving 31 men and 10 women (mean age: 31 years), presenting with autoimmune or systemic diseases, metabolic disorders, thrombophilia, congenital or acquired malformations or organ failure, miscellaneous nephropathies, or hemogram abnormalities. Four patients were taking immunosuppressive agents, 3 biologics, and 4 anticoagulants. Among the 15 civilians requiring medical fitness assessment to enlistment, 6 were declared fit. They presented with a history of juvenile idiopathic arthritis with intermediate uveitis without relapse for 7 years, Mayer-Rokitansky-Küster-Hauser syndrome type II with ectopic kidney, solitary kidney with normal renal function and with hypertension, isolated proteinuria, proteinuria with microscopic hematuria, and muscular fibrolipoma with a history of surgical treatment of a vascular malformation. Among the 26 patients already enlisted in the armed forces, 9 were referred for assessment of medical fitness to serve overseas. Two soldiers were assessed as fit without restrictions; one presented with a history of a single episode of deep vein thrombosis after surgery, and the other had a history of monoclonal gammopathy of renal significance without relapse and without treatment for 8 years. Four soldiers were assessed as fit only for overseas territories with sanitary structures similar to mainland France. They presented with immunoglobulin A (IgA) nephropathy and treatment with angiotensin-converting enzyme inhibitor, mevalonate kinase deficiency and treatment with anakinra, chronic idiopathic thrombocytopenic purpura, and history of unilateral partial renal infarction. The 17 other soldiers were referred for dispensation, long-sickness leave granting, or for specification toward administrative coding of their disease. CONCLUSIONS: We have described the first exhaustive study of specialized fitness decisions referred to an internal medicine department. One-third of the referred patients were declared fit to serve in the armed forces. Further studies are needed to confirm these results, as our study was monocentric. Fitness decisions must take into account the disease, the treatment, and the operational field characteristics. Soldiers with systemic diseases controlled by immunosuppressive agents can serve in tropical areas if they can reach adequate sanitary structures in a short time. The knowledge of systemic diseases as well as the skillfulness of the internists, which are regularly projected to the operational fields, allows them to provide pragmatic fitness expertise to myriad complex situations.

Effect of Mesenchymal Stromal Cells on T Cells in a Septic Context: Immunosuppression or Immunostimulation?

Sepsis is a complex process, including a first wave of damage partially due to the body's response to pathogens, followed by a phase of immune cell dysfunction. The efficacy of a pharmacological approach facing a rapidly evolving system implies a perfect timing of administration-this difficulty could explain the recent failure of clinical trials. Mesenchymal stromal cells (MSCs) are usually defined as immunosuppressive and their beneficial effects in preclinical models of acute sepsis have been shown to rely partly on such ability. If nonregulated, this phenotype could be harmful in the immunosuppressed context arising hours after sepsis onset. However, MSCs being environment sensitive, we hypothesized that they could reverse their immunosuppressive properties when confronted with suffering immune cells. Our objective was to evaluate the effect of human MSCs on activated human lymphocytes in an in vitro endotoxemia model. Peripheral blood mononuclear cells (PBMCs) underwent a 24-h lipopolysaccharide (LPS) intoxication and were stimulated with phytohemagglutinin (PHA) in contact with MSCs. MSCs induced a differential effect on lymphocytes depending on PBMC intoxication with LPS. Unintoxicated lymphocytes were highly proliferative with PHA and were inhibited by MSCs, whereas LPS-intoxicated lymphocytes showed a low proliferation rate, but were supported by MSCs, even when monocytes were depleted. These data, highlighting MSC plasticity in their immunomodulatory activity, pave the way for further studies investigating the mechanisms of mutual interactions between MSCs and immune cells in sepsis. Thus, MSCs might be able to fight against both early sepsis-induced hyperinflammatory response and later time points of immune dysfunction.

Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis.

AIM: The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. PATIENTS AND METHODS: Participants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)1 a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. RESULTS: Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24-117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). CONCLUSION: Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable the continued administration of ICIs. Studies designed to identify at-risk patients are warranted.