Post-CMV Guillain-Barré Syndrome with Anti-GM2 Antibodies: Two Cases and a Review of the Literature.

INTRODUCTION: Guillain-Barré syndrome (GBS) is an acute post-infectious inflammatory polyneuropathy of ubiquitous distribution. Cytomegalovirus (CMV) is the virus that is most frequently involved. All ages are affected but rare pediatric cases seem to show some distinctive features in terms of specificity and severity. Specific antibodies that target the peripheral nervous system have been identified in several forms of GBS in adults, such as anti-GM2 ganglioside antibodies in post-CMV GBS, which in most instances present as demyelinating polyneuropathies, with a more favorable progression and fewer complications. MATERIALS AND METHODS: This is a retrospective report on two cases of post-CMV GBS with a demyelinating disorder and positive for anti-GM2 IgM. The review of the literature examines five other cases of children with post-CMV GBS with anti-GM2 IgM. RESULTS: In terms of progression, our two cases of post-CMV GBS with a demyelinating disorder and anti-GM2 IgM are similar to the five other cases described in the literature. The CMV infection was asymptomatic or paucisymptomatic and involved girls (6/7), often presenting severe motor forms with frequent loss of the ability to walk (4/6), facial involvement (⅗), little respiratory involvement (⅙), and favorable progression with adapted treatment. CONCLUSION: Post-CMV GBS with anti-GM2 IgM is a specific clinical spectrum that seems to affect children as it affects adults with a predominance among females, demyelination, and severe motor involvement, but a good prognosis. On the other hand, unlike adults, the use of assisted ventilation does not seem to be more frequent.

Effectiveness of Immune Checkpoint Inhibitors in Transplant Recipients with Progressive Multifocal Leukoencephalopathy.

Antibodies against PD1 have been used to treat progressive multifocal leukoencephalopathy (PML), a rare brain disease caused by JC virus. We used these antibodies (nivolumab) to treat PML in 3 kidney transplant recipients. All died within 8 weeks of diagnosis. Hence, nivolumab did not improve PML outcome after solid organ transplantation.

Peripheral Plasma and Semen Cytokine Response to Zika Virus in Humans.

We assessed Zika virus RNA and select cytokine levels in semen, blood, and plasma samples from an infected patient in South America. Viral RNA was detected in semen >2 months after viremia clearance; cytokine profiles differed in semen and plasma. After viremia, Zika virus appears to become compartmentalized in the male reproductive tract.

Multirecombinant Enterovirus A71 Subgenogroup C1 Isolates Associated with Neurologic Disease, France, 2016-2017.

In 2016, an upsurge of neurologic disease associated with infection with multirecombinant enterovirus A71 subgenogroup C1 lineage viruses was reported in France. These viruses emerged in the 2000s; 1 recombinant is widespread. This virus lineage has the potential to be associated with a long-term risk for severe disease among children.

Impact of donor BK polyomavirus replication on recipient infections in living donor transplantation.

BACKGROUND: Multiple risk factors for BK polyomavirus (BKPyV) replication after kidney transplantation have been described. Here, we investigated the impact of living donors' urinary BKPyV shedding and recipients' BKPyV antibody status pre-transplant on BKPyV replication during the first year post-transplantation. METHODS: We assessed a cohort of living kidney donors and their paired recipients (n = 121). All donors were tested before transplantation, and recipients were tested before and after transplantation for BKPyV viruria and viremia. BKPyV-specific serology was assessed in all recipients at transplantation. RESULTS: Ten of 121 donors (8.3%) had urinary BKPyV shedding pre-transplant, none had viremia. Overall, 33 (27.3%) recipients developed viruria after transplantation: 7 had received a kidney from a donor with BK viruria (7/10 positive donors) and 26 had received a kidney from a donor without BK viruria (26/111 negative donors; P = .0015). Fifteen (12.4%) recipients developed BK viremia after transplantation: 3 received a kidney from a donor with viruria (3/10 positive donors, 30%) and 12 received a kidney from a donor without viruria (12/111 negative donors, 11%; P = .08). One patient developed proven nephropathy. Ninety-one percent of recipients were seropositive for BKPyV. No relationship between recipients' sero-reactivity at transplantation and post-transplant BKPyV replication was observed. Pre-transplant donor urinary shedding was an independent risk factor for post-transplant BKPyV replication. CONCLUSION: Screening living kidney donors for BKPyV can identify recipients at higher risk for BKPyV replication after transplantation who may benefit from intensified post-transplant screening and treatment strategies.

Zika Virus Infection and Prolonged Viremia in Whole-Blood Specimens.

We tested whole-blood and plasma samples from immunocompetent patients who had had benign Zika virus infections and found that Zika virus RNA persisted in whole blood substantially longer than in plasma. This finding may have implications for diagnosis of acute symptomatic and asymptomatic infections and for testing of blood donations.

Pilot conversion trial from mycophenolic acid to everolimus in ABO-incompatible kidney-transplant recipients with BK viruria and/or viremia.

Immunosuppression using everolimus (EVR) plus low-dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long-term outcomes and impacts of Tac-EVR on the BK virus are reported in ABO-incompatible kidney-transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34-529) days post-transplantation, seven stable ABO-incompatible kidney-transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO-incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow-up, clinical and biological parameters were monitored. The median time from conversion to the last follow-up was 784 (398-866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti-HLA antibodies). At last follow-up, median eGFR was similar in the Tac-MPA versus Tac-EVR group (40 [range: 14-56] vs. 54.5 ml/min/1.73 m(2) [range: 0-128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO-incompatible kidney-transplant recipients with an active BK virus infection may benefit from conversion to EVR.

Prophylaxis versus pre-emptive treatment for prevention of cytomegalovirus infection in CMV-seropositive orthotopic liver-transplant recipients.

This study compared the pre-emptive and the prophylactic strategies used to prevent cytomegalovirus (CMV) infection and disease in CMV-seropositive orthotopic liver-transplant recipients and searched for associated predictive factors. Seventy-three orthotopic liver-transplant recipients who had received a transplant before November 2005 were given ganciclovir IV pre-emptively (group I) and 56 recipients who had received a transplant after November 2005 were given prophylactic valganciclovir for 3 months (group II). Demographic and biochemical parameters did not statistically vary between the groups at baseline. Monitoring of CMV DNAemia was similar in both groups. Forty-two (57.5%) patients presented with CMV infection in group I and 18 (32.1%) in group II (P < 0.004). CMV DNAemia was first detected at a median of 33 days post-transplant in group I and at 98.5 days in group II (P < 0.003), but viral loads were not significantly different. The overall incidence of CMV disease was 9.6% in group I versus 7.1% in group II (ns). Thirty-five (47.9%) patients presented with biopsy-proven acute rejection in group I and 13 (23.2%) in group II (P = 0.004). Forty (55%) patients in group I and 25 (44.6%) in group II presented with de novo post-transplant diabetes (P = 0.057). At 1-year post-transplant, global survival curves were not significantly different. Independent factors associated with CMV reactivation were an absence of CMV prophylaxis, CMV serological status of the donor, cold ischemia time, and HLA A + B + DR compatibility. CMV prophylaxis is efficacious and can prevent safely the direct and indirect effects of CMV infection in CMV-seropositive orthotopic liver-transplant recipients.

Virological diagnosis of central nervous system infections by use of PCR coupled with mass spectrometry analysis of cerebrospinal fluid samples.

Viruses are the leading cause of central nervous system (CNS) infections, ahead of bacteria, parasites, and fungal agents. A rapid and comprehensive virologic diagnostic testing method is needed to improve the therapeutic management of hospitalized pediatric or adult patients. In this study, we assessed the clinical performance of PCR amplification coupled with electrospray ionization-time of flight mass spectrometry analysis (PCR-MS) for the diagnosis of viral CNS infections. Three hundred twenty-seven cerebrospinal fluid (CSF) samples prospectively tested by routine PCR assays between 2004 and 2012 in two university hospital centers (Toulouse and Reims, France) were retrospectively analyzed by PCR-MS analysis using primers targeted to adenovirus, human herpesviruses 1 to 8 (HHV-1 to -8), polyomaviruses BK and JC, parvovirus B19, and enteroviruses (EV). PCR-MS detected single or multiple virus infections in 190 (83%) of the 229 samples that tested positive by routine PCR analysis and in 10 (10.2%) of the 98 samples that tested negative. The PCR-MS results correlated well with herpes simplex virus 1 (HSV-1), varicella-zoster virus (VZV), and EV detection by routine PCR assays (kappa values [95% confidence intervals], 0.80 [0.69 to 0.92], 0.85 [0.71 to 0.98], and 0.84 [0.78 to 0.90], respectively), whereas a weak correlation was observed with Epstein-Barr virus (EBV) (0.34 [0.10 to 0.58]). Twenty-six coinfections and 16 instances of uncommon neurotropic viruses (HHV-7 [n = 13], parvovirus B19 [n = 2], and adenovirus [n = 1]) were identified by the PCR-MS analysis, whereas only 4 coinfections had been prospectively evidenced using routine PCR assays (P < 0.01). In conclusion, our results demonstrated that PCR-MS analysis is a valuable tool to identify common neurotropic viruses in CSF (with, however, limitations that were identified regarding EBV and EV detection) and may be of major interest in better understanding the clinical impact of multiple or neglected viral neurological infections.

Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells.

A primary HCMV infection or virus reactivation may cause severe disease in hosts with a deficient immune system. The virus can disturb both innate and adaptive immunity by targeting dendritic cell (DC) functions. Monocytes, the precursors of DCs in vivo (MoDCs), are the primary targets of HCMV; they can also harbor latent virus. The DCs generated from infected monocytes (CMV-MoDCs) have an altered phenotype and functional defects. We have shown that CMV-MoDCs do not secrete IL-12 in response to lipopolysaccharide stimulation, cannot ingest dead cells, induce T(H)1 differentiation, or the proliferation of naive allogeneic CD4(+) T cells. We found that the GM-CSF signaling in an entire population of CMV-MoDCs was impaired, although only half of the cells were productively infected, and that IL-6 secretion and suppressors of cytokine signaling 3 induction contributed to this bystander effect. We also showed that MoDCs derived ex vivo from monocytes of viremic patients had the same altered phenotype as CMV-MoDCs, including decreased STAT5 phosphorylation, indicating defective GM-CSF signaling. We have thus described a new mechanism of HCMV-induced immunosupression, indicated how infection may disturb both GM-CSF-dependent physiologic processes and proposed GM-CSF-based therapeutic approaches.

Performance of a rapid molecular multiplex assay for the detection of influenza and picornaviruses.

BACKGROUND: Multiplex assays are a new strategy for diagnosing respiratory infections. These assays are better than those based on cultures or antigen detection, but few data are available for comparing them to monoplex polymerase chain reactions (PCRs). This study evaluated the performance of the Luminex xTAG Respiratory Viral Panel (RVP) Fast assay with reference to 2 real-time PCR assays for detecting type A influenza H1 viruses and human enteroviruses and rhinoviruses. METHODS: This was an analysis of nasal swab specimens obtained from 590 outpatients suffering from acute respiratory tract disease between September 2009 and February 2010. RESULTS: The RVP Fast assay performed well in less than 4 h for detecting type A influenza H1 viruses, particularly (H1N1)pdm09, and human entero/rhinoviruses, with 95.2% and 90.05% agreement, respectively, when compared to monoplex real-time PCR assays. This multiplex assay also detected at least 1 virus in 69.3% of the specimens and detected multiple infections in 40 samples. CONCLUSIONS: The multiplex assay detected clinically important viruses in a single genomic test. It will thus be useful for detecting several viruses causing respiratory tract disorders.

Drug-resistant cytomegalovirus in transplant recipients: a French cohort study.

OBJECTIVES: Cytomegalovirus (CMV) drug resistance is a therapeutic challenge in the transplant setting. No longitudinal cohort studies of CMV resistance in a real-life setting have been published in the valganciclovir era. We report findings for a French multicentre prospective cohort of 346 patients enrolled at initial diagnosis of CMV infection (clinical trial registered at clinicaltrials.gov: NCT01008540). PATIENTS AND METHODS: Patients were monitored for detection of CMV infection for ≥2 years. Real-time detection of resistance by UL97 and UL54 gene sequencing and antiviral phenotyping was performed if viral replication persisted for >21 days of appropriate antiviral treatment. Plasma ganciclovir assays were performed when resistance was suspected. RESULTS: Resistance was suspected in 37 (10.7%) patients; 18/37 (5.2% of the cohort) had virological resistance, associated with poorer outcome. Most cases involved single UL97 mutations, but four cases of multidrug resistance were due to UL54 mutations. In solid organ transplant recipients, resistance occurred mainly during primary CMV infection (odds ratio 8.78), but also in two CMV-seropositive kidney recipients. Neither CMV prophylaxis nor antilymphocyte antibody administration was associated with virological resistance. CONCLUSIONS: These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure.

Pre-emptive intravenous ganciclovir versus valganciclovir prophylaxis for de novo cytomegalovirus-seropositive kidney-transplant recipients.

This sequential study evaluated two strategies regarding human cytomegalovirus (HCMV) infection/disease in HCMV-seropositive de novo kidney-transplant patients. The first cohort of patients (group 1; n = 132) was monitored sequentially for HCMV DNAemia; if it was positive (a cut-off at 3 log(10) copies/ml), the patient was given pre-emptive IV ganciclovir therapy (10 mg/kg/day for 3 weeks). The second cohort consisted of 150 patients (group 2) who were given valganciclovir (VGC) prophylaxis (900 mg/day) for the first 3 months posttransplantation. During the mean follow-up of at least 2 years for both cohorts, VGC prophylaxis resulted in a significant decrease in both CMV infection (68.9% vs. 33.3%; P < 0.001) and disease (9.8% vs. 2.68%, P = 0.021). Factors associated with HCMV reactivation in multivariate analysis were (i) no HCMV prophylaxis; (ii) recipient's age; (iii) being placed on ciclosporine A and mycophenolic acid from the beginning of transplantation (iv) donor HCMV-seropositivity; and (v) being a male recipient. No cases of ganciclovir resistance were detected in the prophylactic group. HCMV prophylaxis had no impact on 2-year patient/graft survival or on kidney-allograft function. We conclude that VGC-prophylaxis can be reasonably used to treat HCMV-seropositive kidney-transplant recipients.

Evaluation of the Aptima™ transcription-mediated amplification assay (Hologic®) for detecting SARS-CoV-2 in clinical specimens.

BACKGROUND: The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which appeared in late 2019, has been limited by isolating infected individuals. However, identifying such individuals requires accurate diagnostic tools. OBJECTIVE: This study evaluates the capacity of the Aptima™ Transcription-Mediated Amplification (TMA) assay (Hologic® Panther System) to detect the virus in clinical samples. STUDY DESIGN: We compared the Aptima™ assay to two in-house real-time RT-PCR techniques, one running on the Panther Fusion™ module and the other on the MagNA Pure 96 and Light-Cycler 480 instruments. We included a total of 200 respiratory specimens: 100 tested prospectively and 100 retrospectively (25 -ve/75 +ve). RESULTS: The final Cohen's kappa coefficients were: κ = 0.978 between the Aptima™ and Panther Fusion™ assays, κ = 0.945 between the Aptima™ and MagNA/LC480 assays and κ = 0.956 between the MagNA/LC480 and Panther Fusion™ assays. CONCLUSION: These findings indicate that the Aptima™ SARS-CoV-2 TMA assay data agree well with those obtained with our routine methods and that this assay can be used to diagnose coronavirus disease 2019 (COVID-19).

Two Cases of Late-Onset Anti-NMDAr Auto-Immune Encephalitis After Herpes Simplex Virus 1 Encephalitis.

Context: Encephalitis due to herpes simplex virus 1 (HSV-1) was described as a potential trigger for the development of anti-N-methyl-D-aspartate receptor (NMDAr) auto-immune encephalitis (AIE) within a few days to a few weeks after the infection. Methods: We assessed clinical, radiological, and biological diagnoses process, treatment response, and evolution. Cases Reported: We report here cases of a 71-year-old man and a 57-year-old woman presenting anti-NMDAr AIE, respectively, 12 and 7 months after HSV-1 encephalitis. In both cases, the onset was brisk, and the symptoms were mainly neuropsychiatric (paranoid delirium, Capgras, and Cotard syndromes) and cognitive, with anterograde amnesia. Relapse of HSV encephalitis, epilepsy, and paraneoplastic neurologic syndromes were excluded. The clinical response to first-line treatments composed of intravenous immunoglobulins and high-dose corticosteroids was poor, whereas significant improvement was noticed after rituximab induction. Conclusion: Post-herpetic anti-NMDAr AIE could arise several months after infection. Clinicians must be aware of this possibility, particularly if cognitive and/or psychiatric symptoms occurred after a remitting period. In our two cases, only rituximab was associated with clinical improvement.

Unusual presentation of cytomegalovirus infection in patients after organ transplant.

OBJECTIVES: Cytomegalovirus (CMV) infection has an enormous impact in solid-organ transplant patients. In immunocompromised patients, CMV is associated with well-known direct effects. We herein describe 3 unusual patterns occurring in the setting of tissue-invasive CMV associated with high viral load. MATERIALS AND METHODS: Of our 3 cases, the first patient after kidney transplant presented with cholestasis related to radiological cholangitis; the second patient after heart transplant presented with erythema nodosum with CMV infection as the sole cause; and the third patient after kidney transplant presented with acute renal failure related to mild interstitial nephritis with acute tubular necrosis and tubulitis. RESULTS: The first patient's cholestasis resolved with antiviral therapy, as did the erythema nodosum and CMV infection of the heart transplant patient. The third patient's acute renal failure resolved by increased steroid dosage, plasma exchanges, and ganciclovir therapy. CONCLUSIONS: These 3 unusual presentations of tissue invasive CMV had favorable outcomes with antiviral therapy.

Acute transverse myelitis following an opsoclonus-myoclonus syndrome: An unusual presentation.

Opso-myoclonus syndrome (OMS) is a very rare and severe condition. Ataxia, opsoclonus, myoclonus and/or behavioral and sleeping disturbances define that autoimmune disorder syndrome which is paraneoplastic or triggered by an infection. Here, we report a 3 year-old immunocompetent boy who developed an atypical OMS which was later complicated by an acute transverse myelitis. Screening for neuroblastoma was negative and extensive infectious screening revealed an active HHV-6 infection confirmed by blood and cerebrospinal fluid PCR. A parainfectious disease was suggested and immunosuppressive treatment was initiated. After 2 years of follow-up, the patient has a left leg paresia needing a splint and is otherwise normal. Transverse myelitis can be associated with parainfectious OMS and earlier immunosuppressive treatment in these cases may be useful especially in young and immunocompetent children.

Zoster after Cyclophosphamide for Systemic Lupus Erythematosus or Vasculitis: Incidence, Risk Factors, and Effect of Antiviral Prophylaxis.

OBJECTIVE: To assess the incidence and the risk factors for zoster in patients exposed to intravenous cyclophosphamide (CYC) for systemic vasculitis or systemic lupus erythematosus (SLE), as well as the protective effect of prophylaxis by valacyclovir (VCV). METHODS: This retrospective study included all adults treated by intravenous CYC for SLE or systemic vasculitis between 2011 and 2015 at Toulouse University Hospital, France. Zoster occurrence was recorded using medical chart review, laboratory data, and patient interviews. Univariate Cox models were computed to assess the risk factors for zoster and the protective effect of prophylaxis by VCV. RESULTS: The cohort consisted of 110 patients (81 systemic vasculitis and 29 SLE). During a mean followup of 3.4 years after CYC initiation, 10 cases of zoster occurred, leading to an overall incidence of 27.9/1000 patient-years (95% CI 15.2-50.6); it was 59.4/1000 patients (95% CI 27.5-123.6) during the year after CYC initiation. Four patients experienced persistent postherpetic neuralgia. Probable risk factors were lymphopenia < 500/µl at CYC initiation (HR 5.11, 95% CI 0.94-27.93) and female sex (HR 4.36, 95% CI 0.51-37.31). The incidence was higher in patients with SLE (HR as compared with systemic vasculitis patients = 2.68, 95% CI 0.54-13.26). None of the 19 patients exposed to VCV during the followup developed zoster. CONCLUSION: The incidence of zoster is high in systemic vasculitis and in patients with SLE exposed to intravenous CYC. CYC may favor postherpetic neuralgia. Prophylaxis by VCV should be considered, particularly in cases of lymphopenia < 500/µl at CYC initiation and during the year after.