Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses

IntroductionCOVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood.MethodsHere, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease.ResultsIn this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form.DiscussionKnowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters.Trial registration numbershttps://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594

Late diagnosis of chronic hypocalcemia due to autoimmune hypoparathyroidism.

International audienceHypoparathyroidism is most often the result of postsurgical damage to the parathyroid glands but may occasionally be autoimmune hypoparathyroidism. In the latter context, activating antibodies directed against the calcium‐sensing receptor (CaSR) have been described. We hereby present the case of a patient suffering from chronic recurrent muscle cramps and paresthesia, presenting for a seizure due to hypocalcaemia. After eliminating the possibility of a genetic disorder, we searched for autoimmune hypoparathyroidism as there was no obvious cause of hypoparathyroidism. The search for anti-CaSR antibodies was positive. There was no argument for autoimmune polyendocrine syndrome type 1 so we concluded that it was isolated autoimmune hypoparathyroidism caused by activating antibodies to the CaSR. The patient was treated with vitamin D and calcium supplementation. The search for complications of hypoparathyroidism and hypercalciuria revealed basal ganglia calcification. The patient’s hypocalcaemia is now being kept under control with oral supplementation

C5b-9 Glomerular Deposits Are Associated With Poor Renal Survival in Membranous Nephropathy

International audienceIntroduction: Membranous nephropathy (MN) is the first cause of nephrotic syndrome in patients without diabetes. Its prognosis is variable, and treatment remains controversial because of potential toxicity. Currently, there is no reliable prognostic marker common to all etiologies of MN and routinely available to predict the disease course and guide therapeutic management. Despite the major role of complement in the glomerular damage of MN, its prognostic impact has never been studied. We investigated the frequency and prognostic impact of glomerular deposition of C5b-9 in MN.Methods: We retrospectively selected adults diagnosed with MN (primary or secondary) at Montpellier University Hospital between December 2004 and December 2015. To be included, all patients were required to have complete medical data and a kidney tissue sample for further immunohistochemistry. We performed PLA2R1, C4d, and C5b-9 staining by immunohistochemistry.Results: Sixty-four adults were included: 45 with primary MN and 19 with secondary MN. C4d was positive in the glomeruli of 61 adults (95.3%). Twenty-nine adults (45.3%) had glomerular deposition of C5b-9. Patients with glomerular deposition of C5b-9 had more severe nephrotic syndrome on diagnosis and lower remission and renal survival rates than adults without.Conclusion: C5b-9 glomerular staining is a powerful and easily accessible tool for stratifying adults according to their renal prognosis. The efficacy of complement inhibitors should be tested in adults with glomerular deposition of C5b-9

Optimization of Rituximab Therapy in Adult Patients With PLA2R1-Associated Membranous Nephropathy With Artificial Intelligence

International audienceIntroduction: Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 μg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients’ characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission.Methods: Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets.Results: The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (P < 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission.Conclusion: This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission

Contactin-1 is a novel target antigen in membranous nephropathy associated with chronic inflammatory demyelinating polyneuropathy

International audiencePrimary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound conactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-conactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated

Image_2_Low baseline IFN-γ response could predict hospitalization in COVID-19 patients.jpeg

The SARS-CoV-2 infection has spread rapidly around the world causing millions of deaths. Several treatments can reduce mortality and hospitalization. However, their efficacy depends on the choice of the molecule and the precise timing of its administration to ensure viral clearance and avoid a deleterious inflammatory response. Here, we investigated IFN-γ, assessed by a functional immunoassay, as a predictive biomarker for the risk of hospitalization at an early stage of infection or within one month prior to infection. Individuals with IFN-γ levels below 15 IU/mL were 6.57-times more likely to be hospitalized than those with higher values (p65 years, and no vaccination were independently associated with hospitalization. In addition, we found a significant inverse correlation between low IFN-γ response and high level of IL-6 in plasma (Spearman’s rho=-0.38, p=0.003). Early analysis of the IFN-γ response in a contact or recently infected subject with SARS-CoV-2 could predict hospitalization and thus help the clinician to choose the appropriate treatment avoiding severe forms of infection and hospitalization.</p