Inflammatory progressive multifocal leukoencephalopathy with human T-cell lymphotropic virus-1 coinfection.

A middle-aged man with progressive multifocal leukoencephalopathy (PML) in a human T-cell lymphotropic virus type-1 (HTLV-1) carrier on haemodialysis presented with mild dysarthria and ataxia. Brain MRI revealed asymmetric T2-hyperintense lesions in the cerebral white matter, cerebellum and brainstem. A small amount of JC virus (JCV) genome in cerebrospinal fluid was detected by PCR and cerebellar biopsy demonstrated JCV-DNA presence. Pathological findings showed demyelinating lesions and glial cells with mildly enlarged nuclei, accompanied by T-lymphocytes, neutrophils and plasma cell infiltration. The CD4+/CD8+ratio was 0.83. High-dose corticosteroid therapy was effective for inflammatory PML lesions, and the administration of mefloquine combined with mirtazapine led to favourable outcome. The encephalitis in this case is considered to have occurred secondarily to JCV infection in the presence of HTLV-1 infection. Therefore, it is crucial to investigate the presence of HTLV-1 in order to understand the aetiology of this brain inflammation.

Molecular monitoring of viral infections in immunocompromised patients in a large university hospital in Italy: reflections after thirteen years of real-life activity.

PURPOSE: This study aimed to investigate the prevalence and viral reactivations of clinical interest in the immunocompromised patient with particular focus on hematologic and solid organ transplant recipients. METHODS: Molecular screening data of CMV, EBV, JCV and BKV from 2011 to 2023 were analyzed. This extensive time span allowed the access to more than 100,000 samples from over 20,000 patients treated at Policlinico Umberto I. It was possible to temporally investigate patient attendance patterns, average age distribution, seasonality of infections, and positivity rates of the analyzed viruses. RESULTS: Between 2019 and 2022 a significant reduction in organ transplants performed and in the positive molecular detection of EBV, JCV and BKV was observed. Additionally, there has been a noteworthy decrease in CMV reactivations, with a reduction of up to 50% starting in 2019. A remarkable reduction of 39% in the rate of CMV viral reactivation has been also achieved in SOT between 2016 and 2023. CONCLUSION: The years following 2019 were profoundly impacted by the COVID-19 pandemic era. This period resulted in a substantial reduction in healthcare services and hospital visits. Furthermore, the introduction of the drug Letermovir in Italy in 2019 demonstrated remarkable efficacy, evidenced by a reduction in CMV reactivations. Additionally, the adoption of a novel clinical approach centered on personalized therapy facilitated improved management of immunocompromised patients.

Higher detection of JC polyomavirus in colorectal cancerous tissue after pretreatment with topoisomerase I enzyme; colorectal tissue serves as a JCPyV persistence site.

BACKGROUND: The JC polyomavirus has been blamed to contribute in colorectal cancer (CRC), however, the topic is still controversial. Varying detection rate of JCPyV genome has been reported mainly due to technical reasons. Here, we provide summative data on the topic, with emphasize on technical issues. METHODS: Formalin-fixed paraffin-embedded tissue samples from 50 patients with CRC, consisting of tumoral and non-cancerous marginal tissue (totally 100 samples) were included in the study. After DNA extraction, specific JCPyV T-Ag sequences were targeted using Real-time PCR. To unwind the supercoiled JCPyV genome, pretreatment with topoisomerase I, was applied. Immunohistochemical (IHC) staining was performed using an anti-T-Ag monoclonal antibody. RESULTS: In the first attempts, no samples were found to be positive in Real-time PCR assays. However, JCPyV sequences were found in 60% of CRC tissues and 38% of non-cancerous colorectal mucosa after application of pre-treatment step with topoisomerase I enzyme (P = 0.028). T-Ag protein was found in the nuclear compartment of the stained cells in IHC assays. CONCLUSIONS: The presence of JCPyV in CRC tissues, as well as T-Ag localization in the nucleolus, where its oncogenic effect takes place, may provide supporting evidence for JCPyV involvement in CRC development. The study highlights the importance of using topoisomerase I to enhance JCPyV genome detection. Also, colorectal tissue is one of the permissive human tissue for JC resistance after preliminary infection.

Disease-modifying therapies and progressive multifocal leukoencephalopathy in multiple sclerosis: A systematic review and meta-analysis.

Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.

Biopsy-proven PML in an HIV-negative patient with discoid lupus: Failure to detect JC virus in CSF.

We present a case of a 58-year-old man with a history of severe discoid lupus erythematosus and acute encephalopathy and incoordination. Antinuclear antibody testing was weakly positive but all other laboratory tests for systemic lupus erythematosus were negative and serum quantitative immunoglobulins and lymphocytes were normal. MRI brain showed T2/FLAIR hyperintensities within the bilateral parietal and temporal lobes with involvement of subcortical U fibers. CSF PCR was negative for varicella-zoster virus, herpes simplex, JCV and BK virus. However, JCV antibody index was elevated (3.88; reference: < 0.2). Right parietal brain biopsy was consistent with JCV infection and diagnostic of progressive multifocal leukoencephalopathy (PML). To the best of our knowledge, this is the first reported case of PML in a patient with discoid lupus without other traditional risk factors for the disease and highlights the need for clinical vigilance in this patient population.

Colorectal Carcinoma Affected Patients Are Significantly Poor Responders Against the Oncogenic JC Polyomavirus.

Background: Many investigations reported the association between human tumors and JCPyV, a polyomavirus with oncogenic potential. The association has been supported by studies that found JCPyV footprints in CRC and gliomas of different types. Indeed, JCPyV footprints including its nucleic acids and Tag oncoprotein have been revealed in CRC tissues. Methods: Herein, sera from colorectal carcinoma (CRC) affected patients and healthy individuals (HS), employed as control, were analysed for immunoglobulin G (IgG) antibodies against specific JCPyV viral capsid protein 1 (VP1) antigens. The investigation was carried out employing an innovative immunological assay. Indeed, an indirect enzyme-linked immunosorbent assay (ELISA) with JCPyV VP1 mimotopes was used. JCPyV VP1 mimotopes consisted of synthetic peptides mimicking VP1 epitopes. Results: Sera from CRC affected patients, evaluated using indirect ELISAs with synthetic mimotopes, showed a significant lower prevalence of IgG antibodies against JCPyV VP1 mimotopes (26%) compared to HS (51%), p<0.005. These data were confirmed by another method, the hemagglutination inhibition (HAI) assay. Altogether these results, i.e. the prevalence of serum IgG antibodies against JCPyV VP1 mimotopes from patients with CRC is approximately 50% lower than in HS, are of interest. Discussion: Our data suggest that patients with CRC are significantly poor responders against JCPyV VP1 antigens. It is possible that CRC patients are affected by a specific immunological deregulation. This immunological dysfunction, revelled in CRC patients, may account for their predisposition to the colorectal carcinoma onset.

CROI 2021: Neurologic Complications of HIV-1 Infection or COVID-19.

The 2021 Conference on Retroviruses and Opportunistic Infections (CROI) featured a timely review of the neurologic complications of COVID-19 as well as new research findings on mechanisms by which SARS-CoV-2 may affect the brain. CROI included new and important findings about the neurologic complications of HIV-1, human polyomavirus 2 (also known as JC Virus), and cryptococcus. New long-term analyses of cognition in people with HIV-1 identified that cognitive decline over time is associated with multimorbidity, particularly diabetes, chronic lung disease, and vascular disease risk conditions. These conditions are associated with aging, and the question of whether people with HIV are at risk for premature aging was addressed by several reports. New findings from large analyses of resting state networks also provided valuable information on the structural and functional networks that are affected by HIV-1 infection and cognitive impairment. Several reports addressed changes after initiating or switching antiretroviral therapy (ART). Findings that will improve understanding of the biologic mechanisms of brain injury in people with HIV were also presented and included evidence that host (eg, myeloid activation, inflammation, and endothelial activation) and viral (eg, transcriptional activity and compartmentalization) factors adversely affect brain health. Other research focused on adjunctive therapies to treat HIV-1 and its complications in the central nervous system. This summary will review these and other findings in greater detail and identify key gaps and opportunities for researchers and clinicians.

Prevalence and genotype distribution of JC polyomavirus in urine from patients with hematological malignancies in Vietnam.

JC virus (JCV) causes progressive multifocal leukoencephalopathy in immunocompromised patients. The prevalence and genotype patterns of JCV vary between different geographical regions. This study was done to investigate the prevalence and genotype distribution of JCV in patients with hematological malignancies in Vietnam. A total of 48 urine samples were collected from patients with hematological malignancies. DNA was extracted and detection of JCV was by nested-polymerase chain reaction. Sequence analysis was obtained and a phylogenetic tree was constructed for genotyping of JCV. Twenty-seven (56.25%) urine samples tested positive for JCV. JCV genotype 7 was only observed in this study. Subtype analysis showed that JCV subtype 7A was the most commonly prevalent, followed by 7B1 and 7C1. Other subtypes were not detected in this population. There were no significant differences associated with age, gender, and biochemical parameters between patients with JCV and without JCV excretion in urine. The present study showed a high prevalence of JCV in the urine of patients with hematologic malignancies. The most common genotype found in this population was JCV subtype 7A.

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

A rare urinary JC virus reactivation after long-term therapy with rituximab.

The possible role of JC virus in determining urinary tract involvement has only recently been recognized. The case of a man with laboratory-confirmed JC virus replication in the urine after a maintenance schedule of rituximab administered for a lymphoproliferative disorder is reported herein. The patient developed severe renal and urinary tract impairment, characterized by the onset of nephropathy, bilateral ureteral strictures, and a serious reduction in vesical compliance, ultimately requiring an ileal neobladder configuration. The renal and urinary tract involvement was finally attributed to JC virus reactivation. This observation suggests that renal and urinary tract diseases related to JC virus might be associated with long-term rituximab treatment.

Prevalence of Human Polyomavirus JC and BK in Normal Population.

JC virus (JCV) , and BK virus (BKV) can remain latency in kidney and excrete via urine asymptomatically. JCV has been associated with colorectal and bladder cancers. BKV has been linked with lung, pancreas, liver, urogenital tract, head and neck cancers. Therefore, the frequency of JCV DNA and BKV DNA are essential to evaluate in urine samples of healthy individuals. MATERIALS AND METHODS: Hundred sixty four urine samples were collected from healthy subjects [96 females and 68 males]. DNA was extracted and detection of JCV DNA and BKV DNA was carried out by PCR . The analysis of sequencing and construction of phylogenetic tree were performed for the samples positive for JCV DNA and BKV DNA. RESULTS: Ten (6.09%) urine samples [5/96(5.2%) females and 5/68( 8.82) males] were tested positive for JCV DNA (P= 0.814). The results of sequencing and phylogenetic tree showed the isolated JCV DNA were cluster with 3A genotype. 21/164 (12.8%) samples were tested positive for BKV DNA [11/96(11.45%) females and males 10/68(14.7%)] ( P= 0.63). The results of sequencing and phylogenetic tree showed that the isolated BKV was cluster with genotype III. CONCLUSION: In the present study 6.09% and 12.8% of the healthy individuals showed positive for JCV DNA (genotype 3A) and BKV DNA(genotype III) respectively. With regard to life threating diseases by BKV and JCV in immunocomprsied patients , the screening BKV DNA and JCV DNA should be implemented for patients with cancer /autoimmune diseases /organ recipient/ multiple sclerosis (MS), prior to immunosuppression therapy or immunomodulatory agents treatment.
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Progressive multifocal leukoencephalopathy in an HIV patient was diagnosed by 3 times lumbar punctures and 2 times brain biopsies.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV) and is difficult to diagnose. We report on a male HIV-positive patient with PML finally diagnosed by 3 times lumbar punctures and 2 times brain biopsies. Negative results of JCV-PCR in cerebrospinal fluid (CSF) do not rule out the diagnosis of PML when clinical manifestations and neuroimaging features suspected PML. It is necessary to obtain new CSF and make repeat tests and even perform brain biopsy.

Associations Between Gastric Cancer Risk and Virus Infection Other Than Epstein-Barr Virus: A Systematic Review and Meta-analysis Based on Epidemiological Studies.

INTRODUCTION: Besides Helicobacter pylori and Epstein-Barr virus, other viruses might play potential roles in gastric carcinogenesis. This systematic review and meta-analysis was conducted to compare the prevalence of the viruses between gastric cancer (GC) and any controls. METHODS: Comprehensive literature was searched up to January 25, 2019, and search was updated on April 6, 2020. The studies that compared the prevalence of viruses other than Epstein-Barr virus between GC and healthy or nonmalignant controls were eligible. Stata 12.0 software was used for heterogeneity tests and meta-analyses. Meanwhile, subgroup analysis, sensitivity analysis, and publication bias evaluation were performed where applicable. The power (1-ß) was estimated by the PASS 11 software for each individual study. RESULTS: A total of 41 eligible studies were included, concerning 11 kinds of viruses. Prevalence were significantly higher in GC for hepatitis B virus (odds ratio [OR] = 1.39, 95% confidence interval [CI] 1.11-1.75), human cytomegalovirus (OR = 2.25, 95% CI 1.14-4.43), human papillomavirus (HPV) (OR = 1.63, 95% CI 1.05-2.54), and John Cunningham virus (OR = 2.52, 95% CI 1.26-5.04). In subgroup analyses, HPV-16 infection was significantly associated with GC (OR = 2.42, 95% CI 1.00-5.83). DISCUSSION: This study demonstrated that hepatitis B virus, human cytomegalovirus, HPV, and John Cunningham virus were more prevalent in GC. However, the causal relationship between their infection and risk of GC remains inconclusive, and further investigations are required.

Prevalence of JC and BK viruses in Patients with Colorectal Cancer: A Systematic Review and Meta- Analysis.

INTRODUCTION: Polyomaviruses including BK virus (BKV) and JC virus (JCV) are widespread in human and have been associated with colorectal cancer (CRC) in some studies. The aim of present systematic review and meta-analysis article is to calculate the pooled prevalence of BKV and JCV in patients with CRC and assessing their association with this malignancy. MATERIALS AND METHODS: Domestic databases and Sciences Direct, PubMed, ProQuest, Web of Sciences and Scopus were searched for relevant articles up to 2nd  June 2019Two independent reviewers extracted the related data from eligible articles. The pooled prevalence and pooled odds ratio (POR) and their 95% confidence interval (95% CI) were calculated using "metaprop" and "metan" commands in Stata 14. Where I2 statistics were >50%, the random effect model was used. RESULTS: From 1461 relevant studies, 24 articles were eligible and included in the qualitative while 19 articles included in quantitative analysis. The pooled prevalence based on diagnostic methods varies from 29% using immunohistochemistry to 52% using nested-PCR method. The likelihood of being infected with JCV  was significantly higher in CRC patients compared to healthy (POR: 4.41, 95% CI: 2.13 - 9.13) controls, normal adjacent mucosa (POR: 2.79, 95% CI: 1.3-5.9) and colorectal adenoma (POR: 3.1, 95% CI: 1.5-6.5) but was not significant when non-CRC patients used as control group. CONCLUSION: The prevalence of JCV in colorectal patients was substantially variable by different methods and targets. The significant association between JCV and CRC that was observed in the present study is not indicative of causation and should be studied more in large-scale prospective designs.

Prevalence of progressive multifocal leukoencephalopathy (PML) in adults and children with systemic lupus erythematosus.

OBJECTIVE: To define the risk of progressive multifocal leukoencephalopathy (PML) in SLE. METHODS: This is a retrospective observational study to evaluate PML cases in patients with SLE admitted to two large academic hospitals. Using electronic medical record (EMR) data, International Classification of Diseases (ICD) codes identified PML cases among patients with SLE, rheumatoid arthritis (RA) (controls), had renal transplant and with HIV. Medication exposure was reviewed. RESULTS: A total of 5409 Columbia University Medical Center (CUMC) patients and 2046 Northwell Health patients were identified using one ICD code for SLE. Of 7455 patients, three had an ICD code for PML. On EMR review, however, PML was substantiated in only one fatal SLE case with significant immunosuppressant use and severe lymphopenia (<0.5 cells x 109/L); one patient was evaluated for PML but cerebrospinal fluid (CSF) was negative for JC virus and improved with treatment of central nervous system (CNS) lupus. EMR data were very limited for the third patient and diagnosis could not be confirmed. None of the 13 342 patients with RA ICD codes had PML. Of the 5409 patients with an SLE ICD code at CUMC, 212 also had a renal transplant ICD code, and 83 had concomitant HIV/AIDS. Based on inpatient pharmacy records of 5409 hospitalised patients at CUMC, 59.2% were treated with steroids, and 16.09% with immunosuppressants (7.76% mycophenolate, 3.42% cyclophosphamide, 2.88% azathioprine and 2.03% rituximab). No patients with paediatric SLE (pSLE) (n=538) had PML. The combined prevalence of PML in hospitalised patients with SLE at the two hospitals was 13-27/100 000 patients. CONCLUSION: Among 7455 adult patients with SLE ICD codes, there were two PML cases, with only one confirmed case associated with severe lymphopenia and immunosuppressants, corresponding to a prevalence of 13-27 per 100 000 patients. No PML cases in pSLE were found. A high index of suspicion in patients with SLE and CNS manifestations is required for the prompt diagnosis of PML.

[Progressive Multifocal Leukoencephalopathy Associated with HIV Infection Diagnosed by Brain Biopsy with Repeated Negative PCR Testing of CSF JC Virus DNA].

A 36-year-old man with human immunodeficiency virus (HIV) infection was admitted to our hospital due to progressive ataxia. Brain MRI demonstrated high-signal intensity in the white matter of the right parietal lobe and left cerebellar hemisphere on T2-weighted images. Despite antiretroviral therapy, as his clinical symptoms worsened and MRI lesions gradually increased with the appearance of gadolinium-enhanced lesions, immune reconstitution inflammatory syndrome by progressive multifocal leukoencephalopathy (PML) associated with HIV infection was suspected. However, JC virus (JCV) in the cerebrospinal fluid (CSF) was undetectable by DNA PCR twice. Therefore, biopsy of the right parietal lobe was performed. JCV DNA was detected by PCR using the biopsy sample. JC viral protein was also identified by immunohistochemistry. Brain biopsy should be considered for the clinical diagnosis of PML when CSF JCV is negative on repeated DNA PCR. (Received September 20, 2019; Accepted January 14, 2020; Published May 1, 2020).