Publications by authors named "Morgane Solis"

27 Publications

  • Page 1 of 1

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

Eur J Neurol 2021 Feb 14. Epub 2021 Feb 14.

Plant Imaging and Mass Spectrometry, Institut de biologie moléculaire des plantes, CNRS, Strasbourg, Unistra, France.

Background: COVID-19 affects the brain in various ways, among which delirium is worrying. We assessed whether a specific, long-lasting, COVID-19-related brain injury develops in acute respiratory distress syndrome-patients after life-saving re-oxygenation.

Methods: We studied ten COVID+ patients (COVID+) with unusual delirium associated with neuroimaging suggestive of diffuse brain injury, and seven controls with non-COVID encephalopathy. The assessment took place when the intractable delirium started at weaning off ventilation support. We performed brain magnetic resonance imaging (MRI), followed by standard cerebrospinal fluid (CSF)-analyses and assessment of CSF-erythropoietin (EPO) concentrations (as a marker for the assessment of tissue repair), and of non-targeted CSF-metabolomics using LC-HR-Mass Spectrometry.

Results: Patients were similar as regards severity scores, but COVID+ were hospitalized longer (25 [11.75; 25] versus 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 hemorrhages only in COVID+. In the latter, CSF-EPO concentration was lower (1.73 [1.6; 2.06] versus 3.04 [2.9; 3.91] mUI/ml, p= 0.01), and CSF-metabolomics indicated: a) increased compounds such as foodborne molecules (sequiterpenes), molecules from industrialized beverages, and micro-pollutants (di-ethanolamine); b) decreased molecules 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+ patients 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.
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http://dx.doi.org/10.1111/ene.14776DOI Listing
February 2021

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

Acad Emerg Med 2021 Jan 22. Epub 2021 Jan 22.

INSERM (French National Institute of Health and Medical Research, UMR 1260, Regenerative NanoMedicine (RNM), Fédération de Médecine Translationnelle (FMTS), University of Strasbourg, Strasbourg, France.

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) log 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.
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http://dx.doi.org/10.1111/acem.14217DOI Listing
January 2021

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

Viruses 2020 12 2;12(12). Epub 2020 Dec 2.

Virology Laboratory, Strasbourg University Hospitals, 67000 Strasbourg, France.

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.
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http://dx.doi.org/10.3390/v12121380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761562PMC
December 2020

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

Am J Transplant 2021 03 28;21(3):1295-1303. Epub 2021 Jan 28.

Department of Infectious Diseases, Strasbourg University Hospital, Strasbourg, France.

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.
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http://dx.doi.org/10.1111/ajt.16424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753418PMC
March 2021

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

Med Hypotheses 2020 Nov 23;144:110025. Epub 2020 Jun 23.

Pôle de Psychiatrie, Santé Mentale et Addictologie, Hôpitaux Universitaires de Strasbourg, France; Laboratoire de Psychologie des Cognitions, Université de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1016/j.mehy.2020.110025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309834PMC
November 2020

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

J Infect Dis 2021 02;223(4):600-609

Service d'Imagerie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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.
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http://dx.doi.org/10.1093/infdis/jiaa745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798956PMC
February 2021

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

Eur Radiol 2020 Nov 6. Epub 2020 Nov 6.

Hôpitaux Universitaires de Strasbourg, Service d'imagerie 2, Hôpital de Hautepierre, Strasbourg, France.

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.
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http://dx.doi.org/10.1007/s00330-020-07362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644389PMC
November 2020

Progressive multifocal leukoencephalopathy and sarcoidosis under interleukin 7: The price of healing.

Neurol Neuroimmunol Neuroinflamm 2020 09 11;7(5). Epub 2020 Aug 11.

From the Department of Clinical Immunology and Internal Medicine (A.G., V.G, Y.D., V.P., T.M., A.-S.K.), National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital; Université de Strasbourg (A.G., M.S., V.G., Y.D., T.M., A.-S.K.), INSERM UMR - S1109; Université de Strasbourg (A.G., M.S., Y.D., C.L., Y.H., T.M., A.-S.K.), Faculty of Medicine; Virology Laboratory (M.S.), Strasbourg University Hospital; Université de Strasbourg (V.G.), Faculty of Pharmacy, Illkirch, France; Internal Medicine and Intensive Care (C.K.), Strasbourg University Hospital; Department of Dermatology (C.L.), Strasbourg University Hospital; Department of Neurology (L.K.), INSERM U1119, Biopathologie de La Myéline, Neuroprotection et Stratégies Thérapeutiques, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS); Université de Strasbourg (A.M., R.C.), INSERM UMR-S1109, GENOMAX Platform, Fédération Hospitalo-Universitaire OMICARE, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX; Department of Infectious Diseases (Y.H.), Strasbourg University Hospital; and Departement of Pneumology (S.H.), Strasbourg University Hospital, Strasbourg, France.

Objective: To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis.

Methods: Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis.

Results: We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy.

Conclusions: New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus.
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http://dx.doi.org/10.1212/NXI.0000000000000862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428361PMC
September 2020

In-depth virological assessment of kidney transplant recipients with COVID-19.

Am J Transplant 2020 11 12;20(11):3162-3172. Epub 2020 Sep 12.

Department of Virology, Strasbourg University Hospital, Strasbourg, France.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via reverse transcription-polymerase chain reaction and SARS-CoV-2 serology via enzyme-linked immunosorbent assay and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study, we examined hospitalized kidney transplant recipients with nonsevere (n = 21) and severe (n = 19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (P = .010) and mortality (P = .010). All patients harbored antibodies during the second week after symptom onset that persisted for 2 months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.
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http://dx.doi.org/10.1111/ajt.16251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436721PMC
November 2020

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.

Am J Transplant 2021 01 27;21(1):329-337. Epub 2020 Aug 27.

Service de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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 log 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.
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http://dx.doi.org/10.1111/ajt.16233DOI Listing
January 2021

CT lung lesions as predictors of early death or ICU admission in COVID-19 patients.

Clin Microbiol Infect 2020 Oct 24;26(10):1417.e5-1417.e8. Epub 2020 Jul 24.

Department of Infectious Disease, Strasbourg University Hospital, Strasbourg, France.

Objective: The main objective of this study was to investigate the prognostic value of early systematic chest computed tomography (CT) with quantification of lung lesions in coronavirus disease 2019 (COVID-19) patients.

Methods: We studied 572 patients diagnosed with COVID-19 (confirmed using polymerase chain reaction) for whom a chest CT was performed at hospital admission. Visual quantification was used to classify patients as per the percentage of lung parenchyma affected by COVID-19 lesions: normal CT, 0-10%, 11-25%, 26-50%, 51-75% and >75%. The primary endpoint was severe disease, defined by death or admission to the intensive care unit in the 7 days following first admission.

Results: The mean patient age was 66.0 ± 16.0 years, and 343/572 (60.0%) were men. The primary endpoint occurred in 206/572 patients (36.0%). The extent of lesions on initial CT was independently associated with prognosis (odds ratio = 2.35, 95% confidence interval 1.24-4.46; p < 0.01). Most patients with lung involvement >50% (66/95, 69.5%) developed severe disease compared to patients with lung involvement of 26-50% (70/171, 40.9%) and ≤25% (70/306, 22.9%) (p < 0.01 and p < 0.01, respectively). None of the patients with normal CT (0/14) had severe disease.

Conclusion: Chest CT findings at admission are associated with outcome in COVID-19 patients.
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http://dx.doi.org/10.1016/j.cmi.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378475PMC
October 2020

Coronavirus Disease 2019: Associated Multiple Organ Damage.

Open Forum Infect Dis 2020 Jul 21;7(7):ofaa249. Epub 2020 Jun 21.

Service d'Anesthésie-Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

A 56-year-old man presented a particularly severe and multisystemic case of coronavirus disease 2019 (COVID-19). In addition to the common lung and quite common pulmonary embolism and kidney injuries, he presented ocular and intestinal injuries that, to our knowledge, have not been described in COVID-19 patients. Although it is difficult to make pathophysiological hypotheses about a single case, the multiplicity of injured organs argues for a systemic response to pulmonary infection. A better understanding of physiopathology should feed the discussion about therapeutic options in this type of multifocal damage related to severe acute respiratory syndrome coronavirus 2.
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http://dx.doi.org/10.1093/ofid/ofaa249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336548PMC
July 2020

Letter to the Editor concerning "Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy".

Am J Transplant 2019 12 6;19(12):3438-3439. Epub 2019 Nov 6.

Service de Nephrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1111/ajt.15648DOI Listing
December 2019

Tick-borne encephalitis virus: molecular determinants of neuropathogenesis of an emerging pathogen.

Crit Rev Microbiol 2019 Aug 3;45(4):472-493. Epub 2019 Jul 3.

Virology Laboratory, University Hospital of Strasbourg , Strasbourg , France.

tick vector, and a vertebrate reservoir, such as small mammals (rodents, or shrews). Humans are accidentally involved in this transmission cycle. Tick-borne encephalitis (TBE) has been a growing public health problem in Europe and Asia over the past 30 years. The mechanisms involved in the development of TBE are very complex and likely multifactorial, involving both host and viral factors. The purpose of this review is to provide an overview of the current literature on TBE neuropathogenesis in the human host and to demonstrate the emergence of common themes in the molecular pathogenesis of TBE in humans. We discuss and review data on experimental study models and on both viral (molecular genetics of TBEV) and host (immune response, and genetic background) factors involved in TBE neuropathogenesis in the context of human infection.
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http://dx.doi.org/10.1080/1040841X.2019.1629872DOI Listing
August 2019

Intravenous Immunoglobulin Administration Significantly Increases BKPyV Genotype-Specific Neutralizing Antibody Titers in Kidney Transplant Recipients.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Virology Laboratory, Strasbourg University Hospital, Strasbourg, France

BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is one of the major causes of kidney graft dysfunction, and there are no BKPyV-specific antiviral therapies available. BKPyV neutralizing antibodies (NAbs) play key roles in protecting against BKPyV replication and represent a potential therapeutic or preventive strategy. In this study, we evaluated NAb titers in intravenous immunoglobulin (i.v. Ig) preparations and in kidney transplant recipients (KTR) before and after i.v. Ig administration. NAb titers directed against major BKPyV genotypes were measured using a BKPyV pseudovirion system. Thirty-three KTR receiving high (1 g/kg of body weight/day;  = 17) or low (0.4 g/kg/day;  = 16) i.v. Ig doses were included. Median NAb titers in i.v. Ig preparations ranged from 5.9 log 50% inhibitory concentration (IC) for genotype I to 4.1 log IC for genotype IV. A mean of 90% of patients (range, 88% to 100%) displaying low or negative BKPyV NAb titers against genotype I reached 4 log IC after the first i.v. Ig administration. This value was reached by a mean of 44% (range, 13% to 83%) and 19% (range, 0% to 38%) of patients against genotype II and genotype IV, respectively. The benefit of i.v. Ig administration persisted until the following course of treatment (day 22 ± 7 days) for genotypes I and II, and no cumulative effect was observed through the three doses. Our findings demonstrate that i.v. Ig administration results in a significant increase in BKPyV NAb titers in KTR. These and pharmacokinetic data provide the rationale for a proof-of-concept study investigating the efficacy of i.v. Ig for the prevention of BKPyV infection in KTR.
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http://dx.doi.org/10.1128/AAC.00393-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658761PMC
August 2019

[BK-virus and pathophysiology of associated diseases].

Virologie (Montrouge) 2019 02;23(1):7-22

Hôpitaux universitaires de Strasbourg, Laboratoire de virologie, 3, rue Koeberlé, 67000 Strasbourg, France, Université de Strasbourg, Inserm, UMR-S 1109, 3, rue Koeberlé, 67000 Strasbourg, France.

BK virus (BKV) is a widely distributed polyomavirus in the world population. It is the causative agent of BKV-associated nephropathy in kidney transplant recipients and hemorrhagic cystitis in bone marrow transplant patients. To date, there is no specific antiviral treatment against BKV. A better understanding of the pathophysiology of BKV-associated diseases, especially in immunocompromised patients, may contribute to the development of novel preventive and therapeutic strategies. After a detailed description of the genomic characteristics of the virus, its replication cycle and available model systems, the pathophysiological and immune mechanisms involved in BKV infection are developed and discussed in this review.
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http://dx.doi.org/10.1684/vir.2019.0757DOI Listing
February 2019

An unusually high substitution rate in transplant-associated BK polyomavirus in vivo is further concentrated in HLA-C-bound viral peptides.

PLoS Pathog 2018 10 18;14(10):e1007368. Epub 2018 Oct 18.

Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Infection with human BK polyomavirus, a small double-stranded DNA virus, potentially results in severe complications in immunocompromised patients. Here, we describe the in vivo variability and evolution of the BK polyomavirus by deep sequencing. Our data reveal the highest genomic evolutionary rate described in double-stranded DNA viruses, i.e., 10(-3)-10(-5) substitutions per nucleotide site per year. High mutation rates in viruses allow their escape from immune surveillance and adaptation to new hosts. By combining mutational landscapes across viral genomes with in silico prediction of viral peptides, we demonstrate the presence of significantly more coding substitutions within predicted cognate HLA-C-bound viral peptides than outside. This finding suggests a role for HLA-C in antiviral immunity, perhaps through the action of killer cell immunoglobulin-like receptors. The present study provides a comprehensive view of viral evolution and immune escape in a DNA virus.
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http://dx.doi.org/10.1371/journal.ppat.1007368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207329PMC
October 2018

The Authors Reply.

J Am Soc Nephrol 2018 05 21;29(5):1578. Epub 2018 Feb 21.

Virology Laboratory and

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http://dx.doi.org/10.1681/ASN.2018010027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967774PMC
May 2018

Comparison of six commercial tick-borne encephalitis IgM and IgG ELISA kits and the molecular characterization of their antigenic design.

Diagn Microbiol Infect Dis 2018 Apr 22;90(4):286-292. Epub 2017 Dec 22.

Virology Laboratory, University Hospital of Strasbourg, Strasbourg, F-67000, France; INSERM, IRM UMR_S 1109, F-67000 Strasbourg, France.

Tick-borne encephalitis virus (TBEV) diagnosis is mainly based on the detection of viral-specific antibodies in serum. Several commercial assays are available, but published data on their performance remain unclear. We assessed six IgM and six IgG commercial enzyme-linked immunosorbent assay (ELISA) kits (ELISA-1 through ELISA-6) using 94 samples, including precharacterized TBEV-positive samples (n=50) and -negative samples (n=44). The six manufacturers showed satisfactory sensitivity and specificity and high overall agreement for both IgM and IgG. Three manufacturers showed better reproducibility and were the most sensitive (100%) and specific (95.5-98.1%) for both IgM and IgG. Two of them were also in agreement with the clinical interpretation in more than 90% of the cases. All the assays use inactivated virus as antigen, with strains showing approximately 94% homology at the amino acid level. The antigenic format of the assays was discussed to further improve this TBEV diagnostic tool.
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http://dx.doi.org/10.1016/j.diagmicrobio.2017.12.012DOI Listing
April 2018

Neutralizing Antibody-Mediated Response and Risk of BK Virus-Associated Nephropathy.

J Am Soc Nephrol 2018 01 17;29(1):326-334. Epub 2017 Oct 17.

Virology Laboratory and

BK virus-associated nephropathy (BKVAN) causes renal allograft dysfunction. The current management of BKVAN relies on pre-emptive adaptation of immunosuppression according to viral load monitoring. However, this empiric strategy is not always successful. Therefore, pretransplant predictive markers are needed. In a prospective longitudinal study, we enrolled 168 kidney transplant recipients and 69 matched donors. To assess the value of BKV genotype-specific neutralizing antibody (NAb) titers as a predictive marker for BKV replication, we measured BKV DNA load and NAb titers at transplant and followed patients for 24 months. After transplant, 52 (31%) patients displayed BKV replication: 24 (46%) patients were viruric and 28 (54%) patients were viremic, including 13 with biopsy-confirmed BKVAN. At any time, patients with high NAb titers against the replicating strain had a lower risk of developing BKV viremia (hazard ratio [HR], 0.44; 95% confidence interval [95% CI], 0.26 to 0.73; =0.002). Each log increase in NAb titer decreased the risk of developing viremia by 56%. Replicating strains were consistent with donor transmission in 95% of cases of early BKV replication. Genotype mismatch between recipients' neutralization profiles before transplant and their subsequently replicating strain significantly increased the risk of developing viremia (HR, 2.27; 95% CI, 1.06 to 4.88; =0.04). A NAb titer against the donor's strain <4 log before transplant significantly associated with BKV replication after transplant (HR, 1.88; 95% CI, 1.06 to 3.45; =0.03). BKV genotype-specific NAb titers may be a meaningful predictive marker that allows patient stratification by BKV disease risk before and after transplant.
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http://dx.doi.org/10.1681/ASN.2017050532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748919PMC
January 2018

A new hot spot for tick-borne encephalitis (TBE): A marked increase of TBE cases in France in 2016.

Ticks Tick Borne Dis 2018 01 28;9(1):120-125. Epub 2017 Sep 28.

Virology Laboratory, University Hospital of Strasbourg, F-67000 Strasbourg, France; INSERM, IRM UMR_S 1109, F-67000 Strasbourg, France.

Objectives: Tick-borne encephalitis virus (TBEV) is a zoonotic agent causing severe encephalitis. In 2016, in Northeastern France, we faced a TBEV infection increase, leading to a warning from the Regional Health Agency. Here, we report the confirmed TBE cases diagnosed between January 2013 and December 2016, with particular emphasis on the year 2016.

Methods: A total of 1643 blood and cerebrospinal fluid (CSF) samples from everywhere in France, corresponding to 1460 patients, were prospectively tested for anti-TBEV-specific IgM and IgG antibodies by ELISA. Additional 39 blood and CSF samples from patients with suspected Lyme neuroborreliosis were retrospectively investigated.

Results: The TBEV seropositivity rate was estimated to 5.89% and 54 patients were diagnosed as TBE-confirmed cases. A significant increase in TBE cases was observed during the year 2016 with 29 confirmed cases, instead of a mean of eight cases during the three previous years (p=0.0006). Six imported cases and 48 autochthonous cases, located in the Alsace region (n=43) and in the Alpine region (n=5) were reported. Forty-six patients experienced neurological impairment. Nine patients showed an incomplete recovery at last follow-up (from 15days to eight months post-infection). TBE diagnosis was performed earlier for patients taken in charge in the Alsace region than those hospitalized elsewhere in France (p=0.0087). Among the 39 patients with suspected Lyme neuroborreliosis retrospectively investigated, one showed a TBEV recent infection.

Conclusion: The TBE increase that occurred in France in 2016 highlights the need to improve our knowledge about the true burden of TBEV infection and subsequent long-term outcomes.
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http://dx.doi.org/10.1016/j.ttbdis.2017.09.015DOI Listing
January 2018

Problem-based learning in laboratory medicine resident education: a satisfaction survey.

Ann Biol Clin (Paris) 2017 Apr;75(2):181-192

Laboratoire de virologie, Hôpitaux universitaires de Strasbourg, Strasbourg, France.

Theoretical knowledge in biology and medicine plays a substantial role in laboratory medicine resident education. In this study, we assessed the contribution of problem-based learning (PBL) to improve the training of laboratory medicine residents during their internship in the department of virology, Strasbourg University Hospital, France. We compared the residents' satisfaction regarding an educational program based on PBL and a program based on lectures and presentations. PBL induced a high level of satisfaction (100%) among residents compared to lectures and presentations (53%). The main advantages of this technique were to create a situational interest regarding virological problems, to boost the residents' motivation and to help them identify the most relevant learning objectives in virology. However, it appears pertinent to educate the residents in appropriate bibliographic research techniques prior to PBL use and to monitor their learning by regular formative assessment sessions.
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http://dx.doi.org/10.1684/abc.2017.1236DOI Listing
April 2017

45 years after the discovery of human polyomaviruses BK and JC: Time to speed up the understanding of associated diseases and treatment approaches.

Crit Rev Microbiol 2017 Mar 1;43(2):178-195. Epub 2016 Nov 1.

a Laboratoire de Virologie , Hôpitaux Universitaires de Strasbourg , Strasbourg , France.

Nearly 45 years after the discovery of the first two human polyomaviruses BK and JC, their life-long persistence and mechanisms of pathogenesis remain poorly understood and efficient antiviral treatments are severely lacking. In this review, we sought to provide an update on recent advances in understanding the life cycle of these two viruses, particularly focusing on their interaction with the host immune system and pathogenesis. We have also discussed novel treatment approaches and highlighted areas of future research.
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http://dx.doi.org/10.1080/1040841X.2016.1189873DOI Listing
March 2017

In Vitro and In Vivo Models for the Study of Human Polyomavirus Infection.

Viruses 2016 10 22;8(10). Epub 2016 Oct 22.

Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.

Developments of genome amplification techniques have rapidly expanded the family of human polyomaviruses (PyV). Following infection early in life, PyV persist in their hosts and are generally of no clinical consequence. High-level replication of PyV can occur in patients under immunosuppressive or immunomodulatory therapy and causes severe clinical entities, such as progressive multifocal leukoencephalopathy, polyomavirus-associated nephropathy or Merkel cell carcinoma. The characterization of known and newly-discovered human PyV, their relationship to human health, and the mechanisms underlying pathogenesis remain to be elucidated. Here, we summarize the most widely-used in vitro and in vivo models to study the PyV-host interaction, pathogenesis and anti-viral drug screening. We discuss the strengths and limitations of the different models and the lessons learned.
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http://dx.doi.org/10.3390/v8100292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086624PMC
October 2016

Sequence Variation in Amplification Target Genes and Standards Influences Interlaboratory Comparison of BK Virus DNA Load Measurement.

J Clin Microbiol 2015 Dec 14;53(12):3842-52. Epub 2015 Oct 14.

Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Inserm UMR S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France

International guidelines define a BK virus (BKV) load of ≥4 log10 copies/ml as presumptive of BKV-associated nephropathy (BKVN) and a cutoff for therapeutic intervention. To investigate whether BKV DNA loads (BKVL) are comparable between laboratories, 2 panels of 15 and 8 clinical specimens (urine, whole blood, and plasma) harboring different BKV genotypes were distributed to 20 and 27 French hospital centers in 2013 and 2014, respectively. Although 68% of the reported results fell within the acceptable range of the expected result ±0.5 log10, the interlaboratory variation ranged from 1.32 to 5.55 log10. Polymorphisms specific to BKV genotypes II and IV, namely, the number and position of mutations in amplification target genes and/or deletion in standards, arose as major sources of interlaboratory disagreements. The diversity of DNA purification methods also contributed to the interlaboratory variability, in particular for urine samples. Our data strongly suggest that (i) commercial external quality controls for BKVL assessment should include all major BKV genotypes to allow a correct evaluation of BKV assays, and (ii) the BKV sequence of commercial standards should be provided to users to verify the absence of mismatches with the primers and probes of their BKV assays. Finally, the optimization of primer and probe design and standardization of DNA extraction methods may substantially decrease interlaboratory variability and allow interinstitutional studies to define a universal cutoff for presumptive BKVN and, ultimately, ensure adequate patient care.
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http://dx.doi.org/10.1128/JCM.02145-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652096PMC
December 2015

Toward standardization of BK virus monitoring: evaluation of the BK virus R-gene kit for quantification of BK viral load in urine, whole-blood, and plasma specimens.

J Clin Microbiol 2014 Dec 8;52(12):4298-304. Epub 2014 Oct 8.

Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Inserm, U1109, LabEx TRANSPLANTEX, Strasbourg, France Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France

Screening of BK virus (BKV) replication is recommended to identify patients at increased risk of BKV-associated diseases. However, the heterogeneity of molecular techniques hinders the establishment of universal guidelines for BKV monitoring. Here we aimed to compare the performance of the CE-marked BK virus R-gene kit (R-gene) to the performance of our in-house assay for quantification of BKV DNA loads (BKVL). A 12-specimen panel from the Quality Control for Molecular Diagnostics (QCMD) organization, 163 urine samples, and 88 paired specimens of plasma and whole blood (WB) from transplant recipients were tested. Both the R-gene and in-house assays showed a good correlation within the QCMD panel (r = 0.995 and r = 0.989, respectively). BKVL were highly correlated between assays, although positive biases were observed with the in-house assay in analysis of urine (0.72 ± 0.83 log10 copies/ml), plasma (1.17 ± 0.63 log10 copies/ml), and WB (1.28 ± 0.37 log10 copies/ml). Recalibration with a common calibrator significantly reduced the bias in comparisons between assays. In contrast, BKVL was underestimated with the in-house PCR in eight samples containing BKV genotype II, presenting point mutations at primer-annealing sites. Using the R-gene assay, plasma and WB specimens were found to be equally suitable for quantification of BKVL, as indicated by the high correlation coefficient (r = 0.965, P < 0.0001). In conclusion, the R-gene assay demonstrated reliable performance and higher accuracy than the in-house assay for quantification of BKVL in urine and blood specimens. Screening of BKV replication by a well-validated commercial kit may enable clinical laboratories to assess viral loads with greater reproducibility and precision.
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http://dx.doi.org/10.1128/JCM.02031-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313301PMC
December 2014

[RBCs inclusions after splenectomy: not only Howell-Jolly bodies!].

Ann Biol Clin (Paris) 2013 Mar-Apr;71(2):185-9

Service d'hématologie biologique, Pôle laboratoires, CHU de Nancy, France.

We report on several abnormalities of the red blood cells, in particular erythrocytic inclusions, in a 49 year old man. The blood smear presented with marked anisocytosis, target cells, acanthocytes and Howell-Jolly bodies, as well as Pappenheimer bodies and basophilic stippling. These abnormalities can be explained by the clinical context which associated splenectomy, iron overload and severe denutrition. The patient died a few weeks after from kidney and liver insufficiency. We comment on the different features of erythrocytic inclusions and the clinical situations in which they can be found.
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http://dx.doi.org/10.1684/abc.2013.0798DOI Listing
October 2013