Torque teno virus viral load predicts SARS-CoV-2 vaccine response in kidney transplant recipients.

Transplant recipients display poor responses to SARS-CoV-2 mRNA vaccines. In this retrospective study, we investigate torque teno virus (TTV) viral load (VL), a ubiquitous virus reflecting global immune response levels, as a predictive factor of vaccine response in kidney transplant recipients (KTR). Four hundred and fifty-nine KTR having received two SARS-CoV-2 mRNA vaccine doses were enrolled, and 241 of them subsequently received a third vaccine dose. Antireceptor-binding domain (RBD) IgG response was assessed after each vaccine dose and TTV VL was measured in pre-vaccine samples. Prevaccine TTV VL > 6.2 log10 copies (cp)/mL was independently associated with nonresponse to two doses (odds ratio (OR) = 6.17, 95% confidence interval (CI95) = 2.42-15.78) as well as to three doses (OR = 3.62, 95% CI95 = 1.55-8.49). In nonresponders to the second dose, high TTV VL in prevaccine samples or measured before the third dose were equally predictive of lower seroconversion rates and antibody titers. High TTV VL before and during SARS-CoV-2 vaccination schedules are predictive of poor vaccine response in KTR. This biomarker should be further evaluated regarding other vaccine responses.

Association of COVID-19 mortality with serum selenium, zinc and copper: Six observational studies across Europe.

Introduction: Certain trace elements are essential for life and affect immune system function, and their intake varies by region and population. Alterations in serum Se, Zn and Cu have been associated with COVID-19 mortality risk. We tested the hypothesis that a disease-specific decline occurs and correlates with mortality risk in different countries in Europe. Methods: Serum samples from 551 COVID-19 patients (including 87 non-survivors) who had participated in observational studies in Europe (Belgium, France, Germany, Ireland, Italy, and Poland) were analyzed for trace elements by total reflection X-ray fluorescence. A subset (n=2069) of the European EPIC study served as reference. Analyses were performed blinded to clinical data in one analytical laboratory. Results: Median levels of Se and Zn were lower than in EPIC, except for Zn in Italy. Non-survivors consistently had lower Se and Zn concentrations than survivors and displayed an elevated Cu/Zn ratio. Restricted cubic spline regression models revealed an inverse nonlinear association between Se or Zn and death, and a positive association between Cu/Zn ratio and death. With respect to patient age and sex, Se showed the highest predictive value for death (AUC=0.816), compared with Zn (0.782) or Cu (0.769). Discussion: The data support the potential relevance of a decrease in serum Se and Zn for survival in COVID-19 across Europe. The observational study design cannot account for residual confounding and reverse causation, but supports the need for intervention trials in COVID-19 patients with severe Se and Zn deficiency to test the potential benefit of correcting their deficits for survival and convalescence.

Assessment of plasma Catestatin in COVID-19 reveals a hitherto unknown inflammatory activity with impact on morbidity-mortality.

Introduction: Neuroendocrine cells release Catestatin (CST) from Chromogranin A (CgA) to regulate stress responses. As regards COVID-19 patients (COVID+) requiring oxygen supply, to date nobody has studied CST as a potential mediator in the regulation of immunity. Patients & Methods: Admission plasma CST and CgA - its precursor - concentrations were measured (ELISA test) in 73 COVID+ and 27 controls. Relationships with demographics, comorbidities, disease severity and outcomes were analysed (Mann-Whitney, Spearman correlation tests, ROC curves). Results: Among COVID+, 49 required ICU-admission (COVID+ICU+) and 24 standard hospitalization (COVID+ICU-). Controls were either healthy staff (COVID-ICU-, n=11) or COVID-ICU+ patients (n=16). Median plasma CST were higher in COVID+ than in controls (1.6 [1.02; 3.79] vs 0.87 [0.59; 2.21] ng/mL, p<0.03), with no difference between COVID+ and COVID-ICU+. There was no difference between groups in either CgA or CST/CgA ratios, but these parameters were lower in healthy controls (p<0.01). CST did not correlate with either hypoxia- or usual inflammation-related parameters. In-hospital mortality was similar whether COVID+ or not, but COVID+ had longer oxygen support and more complications (p<0.03). CST concentrations and the CST/CgA ratio were associated with in-hospital mortality (p<0.01) in COVID+, whereas CgA was not. CgA correlated with care-related infections (p<0.001). Conclusion: Respiratory COVID patients release significant amounts of CST in the plasma making this protein widely available for the neural regulation of immunity. If confirmed prospectively, plasma CST will reliably help in predicting in-hospital mortality, whereas CgA will facilitate the detection of patients prone to care-related infections.

Torque teno virus DNA load as a predictive marker of antibody response to a three-dose regimen of COVID-19 mRNA-based vaccine in lung transplant recipients.

BACKGROUND: Previous studies have reported that lung transplant recipients (LTR) develop a poor response to two doses of COVID-19 vaccine, but data regarding the third dose are lacking. We investigated the antibody response after three doses of mRNA vaccine in LTR and its predictive factors. METHODS: A total of 136 LTR, including 10 LTR previously infected and 126 COVID-19-naive LTR, were followed during and after three doses of mRNA vaccine. We retrospectively measured anti-receptor-binding domain (RBD) IgG response and neutralizing antibodies. In a posthoc analysis, we used a multivariate logistic regression model to assess the association between vaccine response and patient characteristics, including viral DNA load (VL) of the ubiquitous Torque teno virus (TTV) (optimal cut-off set by ROC curve analysis), which reflects the overall immunosuppression. RESULTS: After 3 doses, 47/126 (37.3%) COVID-19-naive LTR had positive anti-RBD IgG (responders) and 14/126 (11.1%) had antibody titers above 264 Binding Antibody Units/mL. None neutralized the omicron variant versus 7 of the 10 previously infected LTR. Nonresponse was associated with TTV VL ≥6.2 log10 copies/mL before vaccination (Odds Ratio (OR) = 17.87, 95% confidence interval (CI95) = 3.02-105.72), mycophenolate treatment (OR = 4.73, CI95 = 1.46-15.34) and BNT162b2 (n = 34; vs mRNA-1273, n = 101) vaccine (OR = 6.72, CI95 = 1.75-25.92). In second dose non-responders, TTV VL ≥6.2 or <3.2 log10 copies/mL before the third dose was associated with low (0/19) and high (9/10) rates of seroconversion. CONCLUSION: COVID-19-naive LTR respond poorly to three doses of mRNA vaccine, especially those with high TTV VL. Future studies could further evaluate this biomarker as a guide for vaccine strategies.

Case Report: Evolution of Humoral and Cellular Immunity in Two COVID-19 Breakthrough Infections After BNT162b2 Vaccine.

Background: SARS-CoV-2 breakthrough infections after complete vaccination are increasing whereas their determinants remain uncharacterized. Methods: We analyzed two cases of post-vaccination SARS-CoV-2 infections by α and ß variants, respectively. For each participant both humoral (binding and neutralizing antibodies) and cellular (activation markers and cytokine expression) immune responses were characterized longitudinally. Results: The first participant (P1) was infected by an α variant and displayed an extended and short period of viral excretion and symptom. Analysis of cellular and humoral response 72 h post-symptom onset revealed that P1 failed at developing neutralizing antibodies and a potent CD4 memory response (lack of SARS-CoV-2 specific CD4+IL-2+ cells) and CD8 effector response (CD8+IFNγ+ cells). The second participant (P2) developed post-vaccination SARS-CoV-2 infection by a ß variant, associated with a short period of viral excretion and symptoms. Despite displaying initially high levels and polyfunctional T cell responses, P2 lacked initial ß-directed neutralizing antibodies. Both participants developed and/or increased their neutralization activity and cellular responses against all variants, namely, ß and δ variants that lasts up to 3 months after breakthrough infection. Conclusions: An analysis of cellular and humoral response suggests two possible mechanisms of breakthrough infection: a poor immune response to vaccine and viral evasion to neutralizing antibodies.

Combining predictive markers for severe COVID-19: Torquetenovirus DNA load and SARS-CoV-2 RNAemia.

RATIONALE/OBJECTIVES: SARS-CoV-2 is the cause of worldwide COVID-19, which severity has been linked to the immune and inflammatory response. Here, we investigate Torquetenovirus (TTV) DNA load - a marker reflecting the intensity of the overall immune response - as well as SARS-CoV-2 RNAemia and IgM/IgG antibodies in COVID-19-positive patients. METHODS: Two hundred and fifteen COVID-19-positive patients were enrolled, including 87 severe cases and 128 mild-moderate cases. SARS-CoV-2 RNAemia and IgM/IgG antibodies, as well as TTV DNA loads, were measured on longitudinal plasma samples. RESULTS: The rate of severe cases was higher in patients with low TTV DNA load in plasma considering a threshold of 700 copies/mL. In severe patients, SARS-CoV-2 RNAemia positivity rates were higher than those in mild-moderate cases at any timepoint. When combined, TTV DNA load and SARS-CoV-2 RNAemia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR=12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 RNAemia. CONCLUSIONS: TTV DNA load and SARS-CoV-2 RNAemia may be effective, non-invasive markers reflecting disease severity and poor outcome that could be conveniently measured in a clinical laboratory setting, as soon as COVID-19 diagnosis is made.

Epidemiological and clinical insights from SARS-CoV-2 RT-PCR crossing threshold values, France, January to November 2020.

BackgroundThe COVID-19 pandemic has led to an unprecedented daily use of RT-PCR tests. These tests are interpreted qualitatively for diagnosis, and the relevance of the test result intensity, i.e. the number of quantification cycles (Cq), is debated because of strong potential biases.AimWe explored the possibility to use Cq values from SARS-CoV-2 screening tests to better understand the spread of an epidemic and to better understand the biology of the infection.MethodsWe used linear regression models to analyse a large database of 793,479 Cq values from tests performed on more than 2 million samples between 21 January and 30 November 2020, i.e. the first two pandemic waves. We performed time series analysis using autoregressive integrated moving average (ARIMA) models to estimate whether Cq data information improves short-term predictions of epidemiological dynamics.ResultsAlthough we found that the Cq values varied depending on the testing laboratory or the assay used, we detected strong significant trends associated with patient age, number of days after symptoms onset or the state of the epidemic (the temporal reproduction number) at the time of the test. Furthermore, knowing the quartiles of the Cq distribution greatly reduced the error in predicting the temporal reproduction number of the COVID-19 epidemic.ConclusionOur results suggest that Cq values of screening tests performed in the general population generate testable hypotheses and help improve short-term predictions for epidemic surveillance.

Rapid Antigen Test Combined with Chest Computed Tomography to Rule Out COVID-19 in Patients Admitted to the Emergency Department.

OBJECTIVE: Correct and timely identification of SARS-CoV-2-positive patients is critical in the emergency department (ED) prior to admission to medical wards. Antigen-detecting rapid diagnostic tests (Ag-RDTs) are a rapid alternative to Reverse-transcriptase polymerase chain reaction (RT-PCR) for the diagnosis of COVID-19 but have lower sensitivity. METHODS: We evaluated the performance in real-life conditions of a strategy combining Ag-RDT and chest computed tomography (CT) to rule out COVID-19 infection in 1015 patients presenting in the ED between 16 November 2020 and 18 January 2021 in order to allow non-COVID-19 patients to be hospitalized in dedicated units directly. The combined strategy performed in the ED for patients with COVID-19 symptoms was assessed and compared with RT-PCR. RESULTS: Compared with RT-PCR, the negative predictive value was 96.7% for Ag-RDT alone, 98.5% for Ag-RDT/CT combined, and increased to 100% for patients with low viral load. CONCLUSION: A strategy combining Ag-RDT and chest CT is effective in ruling out COVID-19 in ED patients with high precision.

Evolution of antibody responses up to 13 months after SARS-CoV-2 infection and risk of reinfection.

BACKGROUND: Assessment of the kinetics of SARS-CoV-2 antibodies is essential in predicting risk of reinfection and durability of vaccine protection. METHODS: This is a prospective, monocentric, longitudinal, cohort clinical study. Healthcare workers (HCW) from Strasbourg University Hospital were enrolled between April 6th and May 7th, 2020 and followed up to 422 days. Serial serum samples were tested for antibodies against the Receptor Binding Domain (RBD) of the spike protein and nucleocapsid protein (N) to characterize the kinetics of SARS-CoV-2 antibodies and the incidence of reinfection. Live-neutralization assays were performed for a subset of samples before and after vaccination to analyze sensitivity to SARS-CoV-2 variants. FINDINGS: A total of 4290 samples from 393 convalescent COVID-19 and 916 COVID-19 negative individuals were analyzed. In convalescent individuals, SARS-CoV-2 antibodies followed a triphasic kinetic model with half-lives at month (M) 11-13 of 283 days (95% CI 231-349) for anti-N and 725 days (95% CI 623-921) for anti-RBD IgG, which stabilized at a median of 1.54 log BAU/mL (95% CI 1.42-1.67). The incidence of SARS-CoV-2 infections was 12.22 and 0.40 per 100 person-years in COVID-19-negative and COVID-19-positive HCW, respectively, indicating a relative reduction in the incidence of SARS-CoV-2 reinfection of 96.7%. Live-virus neutralization assay revealed that after one year, variants D614G and B.1.1.7, but less so B.1.351, were sensitive to anti-RBD antibodies at 1.4 log BAU/mL, while IgG ≥ 2.0 log BAU/mL strongly neutralized all three variants. These latter anti-RBD IgG titers were reached by all vaccinated HCW regardless of pre-vaccination IgG levels and type of vaccine. INTERPRETATION: Our study demonstrates a long-term persistence of anti-RBD antibodies that may reduce risk of reinfection. By significantly increasing cross-neutralizing antibody titers, a single-dose vaccination strengthens protection against variants. FUN1DING: None.

Factors associated with coinfections in invasive aspergillosis: a retrospective cohort study.

OBJECTIVES: To describe the coinfections in invasive aspergillosis (IA), to identify factors associated with coinfections, and to evaluate the impact of coinfection on mortality. PATIENTS AND METHODS: We conducted a monocentric retrospective study of consecutive putative, probable, or proven IA that occurred between 1997 and 2017. All coinfections, with an onset within 7 days before or after the first sign of aspergillosis, were identified. Factors associated with coinfections and mortality were analysed by multivariable analysis. RESULTS: Among the 690 patients with IA included in the study, the median age was 57 years (range 7 days to 90 years). A coinfection was diagnosed in 272/690 patients (39.4%, 95%CI 35.8-43.2). The location of this coinfection was pulmonary only in 131/272 patients (48%), bloodstream only in 66/272 patients (24%) and other/multiple sites in 75/272 patients (28%). Coinfections were bacterial (110/272 patients, 40%), viral (58/272, 21%), fungal (57/272, 21%), parasitic (5/272, 2%) or due to multiple types of pathogens (42/272, 15%). Factors associated with a coinfection in adjusted analysis were: allogeneic haematopoietic stem-cell transplantation (OR 2.3 (1.2-4.4)), other haematological malignancies (OR 2.1 (1.2-3.8)), other underlying diseases (OR 4.3 (1.4-13.6)), lymphopenia (OR 1.7 (1.1-2.5)), C-reactive protein >180 mg/L (OR 1.9 (1.2-3.0)), fever (OR 2.4 (1.5-4.1)), tracheal intubation (OR 2.6 (1.5-4.7)), isolation of two or more different Aspergillus species (OR 2.7 (1.1-6.3)), and the presence of non-nodular lesions on chest computed tomography (OR 2.2 (1.3-3.7) and OR 2.2 (1.2-4.0)). Coinfections were independently associated with a higher mortality at week 12 (adjusted HR 1.5 (1.1-1.9), p < 0.01). CONCLUSIONS: Coinfections are frequent in IA patients and are associated with higher mortality.

Acute-onset delirium in intensive care COVID patients: association of imperfect brain repair with foodborne micro-pollutants.

BACKGROUND AND PURPOSE: COVID-19 affects the brain in various ways, amongst which delirium is worrying. An assessment was made of whether a specific, long-lasting, COVID-19-related brain injury develops in acute respiratory distress syndrome patients after life-saving re-oxygenation. METHODS: Ten COVID+ patients (COVID+) with unusual delirium associated with neuroimaging suggestive of diffuse brain injury and seven controls with non-COVID encephalopathy were studied. The assessment took place when the intractable delirium started at weaning off ventilation support. Brain magnetic resonance imaging (MRI) was performed followed by standard cerebrospinal fluid (CSF) analyses and assessment of CSF erythropoietin concentrations (as a marker for the assessment of tissue repair), and of non-targeted CSF metabolomics using liquid chromatography high resolution mass spectrometry. RESULTS: Patients were similar as regards severity scores, but COVID+ were hospitalized longer (25 [11.75; 25] vs. 9 [4.5; 12.5] days, p = 0.03). On admission, but not at MRI and lumbar puncture performance, COVID+ were more hypoxic (p = 0.002). On MRI, there were leptomeningeal enhancement and diffuse white matter haemorrhages only in COVID+. In the latter, CSF erythropoietin concentration was lower (1.73 [1.6; 2.06] vs. 3.04 [2.9; 3.91] mIU/ml, p = 0.01), and CSF metabolomics indicated (a) increased compounds such as foodborne molecules (sesquiterpenes), molecules from industrialized beverages and micro-pollutants (diethanolamine); and (b) decreased molecules such as incomplete breakdown products of protein catabolism and foodborne molecules (glabridin). At 3-month discharge, fatigue, anxiety and depression as well as MRI lesions persisted in COVID+. CONCLUSIONS: Some COVID+ are at risk of a specific delirium. Imperfect brain repair after re-oxygenation and lifestyle factors might influence long-lasting brain injuries in a context of foodborne micro-pollutants.

SARS-CoV-2 viral load in nasopharyngeal swabs in the emergency department does not predict COVID-19 severity and mortality.

INTRODUCTION: The ongoing COVID-19 pandemic has led to devastating repercussions on health care systems worldwide. This viral infection has a broad clinical spectrum (ranging from influenza-like disease, viral pneumonia, and hypoxemia to acute respiratory distress syndrome requiring prolonged intensive care unit stays). The prognostic impact of measuring viral load on nasopharyngeal swab specimens (by reverse transcriptase polymerase chain reaction [RT-PCR]) is yet to be elucidated. METHODS: Between March 3 and April 5, 2020, we conducted a retrospective study on a cohort of COVID-19 patients (mild or severe disease) who were hospitalized after presenting to the emergency department (ED) and had at least one positive nasopharyngeal swab during their hospital stay. We led our study at the University Hospitals of Strasbourg in the Greater East region of France, one of the pandemic's epicenters in Europe. RESULTS: We have collected samples from a cohort of 287 patients with a confirmed diagnosis of COVID-19 who were included in our study. Nearly half of them (50.5%) presented a mild form of the disease, while the other half (49.5%) presented a severe form, requiring mechanical ventilation. Median (interquartile range) viral load on the initial upper respiratory swab at admission was 4.76 (3.29-6.06) log10 copies/reaction. When comparing survivors and nonsurvivors, this viral load measurement did not differ according to subgroups (p = 0.332). Additionally, we have found that respiratory viral load measurement was predictive of neither in-hospital mortality (adjusted odds ratio [AOR] = 1.05, 95% confidence interval [CI] = 0.85 to 1.31, p = 0.637) nor disease severity (AOR = 0.88, 95% CI = 0.73 to 1.06, p = 0.167). CONCLUSION: Respiratory viral load measurement on the first nasopharyngeal swab (by RT-PCR) during initial ED management is neither a predictor of severity nor a predictor of mortality in SARS-CoV-2 infection. Host response to this viral infection along with the extent of preexisting comorbidities might be more foretelling of disease severity than the virus itself.

Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients-Results from a proof-of-concept study.

BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR), potentially leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers. We investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log10 against the BKV-specific genotype). Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers ("high-risk") who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers ("high-risk") who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers ("low-risk") who did not receive IVIg (n = 89). At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. We conclude that IVIg may be a valuable strategy for preventing BKV replication.

Is COVID-19 infection more severe in kidney transplant recipients?

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.

Cerebrospinal Fluid Features in Patients With Coronavirus Disease 2019 and Neurological Manifestations: Correlation with Brain Magnetic Resonance Imaging Findings in 58 Patients.

BACKGROUND: Neurological manifestations are common in patients with coronavirus disease 2019 (COVID-19), but little is known about pathophysiological mechanisms. In this single-center study, we examined neurological manifestations in 58 patients, including cerebrospinal fluid (CSF) analysis and neuroimaging findings. METHODS: The study included 58 patients with COVID-19 and neurological manifestations in whom severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction screening and on CSF analysis were performed. Clinical, laboratory, and brain magnetic resonance (MR) imaging data were retrospectively collected and analyzed. RESULTS: Patients were mostly men (66%), with a median age of 62 years. Encephalopathy was frequent (81%), followed by pyramidal dysfunction (16%), seizures (10%), and headaches (5%). CSF protein and albumin levels were increased in 38% and 23%, respectively. A total of 40% of patients displayed an elevated albumin quotient, suggesting impaired blood-brain barrier integrity. CSF-specific immunoglobulin G oligoclonal band was found in 5 patients (11%), suggesting an intrathecal synthesis of immunoglobulin G, and 26 patients (55%) presented identical oligoclonal bands in serum and CSF. Four patients (7%) had a positive CSF SARS-CoV-2 reverse-transcription polymerase chain reaction. Leptomeningeal enhancement was present on brain MR images in 20 patients (38%). CONCLUSIONS: Brain MR imaging abnormalities, especially leptomeningeal enhancement, and increased inflammatory markers in CSF are frequent in patients with neurological manifestations related to COVID-19, whereas SARS-CoV-2 detection in CSF remained scanty.

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

OBJECTIVES: To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. MATERIALS AND METHODS: In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. RESULTS: The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. CONCLUSION: Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. KEY POINTS: • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution "the milky way," and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization "blind spot" was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients' humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances.

An increasing body of evidence suggests a protective effect of some psychoactive substances against SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus type 2). Recent findings suggest that patients with psychiatric disorders are less affected by SARS-CoV-2 than their caregivers, which may seem surprising given some of the frequent risk factors for an unfavorable course of the disease (e.g., obesity, diabetes, cardiovascular and pulmonary diseases). We propose here a mixed pharmacoepidemiological and pharmacochemical hypothesis to explain these findings. A number of psychotropic drugs exhibit activities against coronaviruses (Middle East Respiratory Syndrome coronavirus (MERS-CoV), the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-1) and the Infectious Bronchitis Virus (IBV)) and have been put forward as potentially anti-SARS-CoV-2. These treatments include numerous mee-too drugs (chemically and pharmacologically linked to those which have demonstrated anti-SARS-CoV-2 efficacy) which are frequently prescribed in psychiatric settings. Taken alone or in polypharmacy, these drugs could have a prophylactic anti-SARS-CoV-2 effect, explaining the unexpectedly low proportion of patients with psychiatric disorders and COVID-19. Associated factors such as nicotine can also be considered in the context of a broad chemoprophylactic hypothesis in patients with psychiatric disorders taking different psychoactive substances.