Differential modulation of IL-4, IL-10, IL-17, and IFN-γ production mediated by IgG from Human T-lymphotropic virus-1 (HTLV-1) infected patients on healthy peripheral T (CD4+, CD8+, and γδ) and B cells.

Human T-lymphotropic virus 1 (HTLV-1) infected individuals remain as asymptomatic carriers (ACs) or can develop the chronic neurological disorder HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP) or the adult T-cell leukemia/lymphoma (ATLL), and the immunological mechanisms involved in this pathologies need to be elucidated. Recently, it has been demonstrated that induced or naturally developed IgG repertoires obtained from different groups of donors, grouped by immune status, can modulate human T and B cell functions. Here we aimed to evaluate if the IgG obtained from HTLV-1-infected ACs, HAM/TSP, and ATLL patients can differentially modulate the production of cytokines by human T and B cells. With this purpose, we cultured PBMCs with IgG purified from ACs, HAM/TSP, or ATLL donors and evaluated the frequency and intracellular cytokine production by flow cytometry. Our results indicate that IgG from HAM/TSP patients could induce an augment of IL-17-producing CD4+ T cells, reduce the frequency of IL-4-producing CD4+ T cells, increase IFN-γ-producing CD8+ T cells, and reduce IL-4-producing CD8+ T cells. IgG from ATLL could reduce the frequency of IL-4-producing CD4+ T cells, similarly to IgG from HAM/TSP /TSP, and could reduce the frequency of IFN-γ-producing γδT cells without influence on IL-17- and IL4-producing γδT and could reduce the frequency of IL-10- producing B cells. Finally, IgG from both HAM/TSP and ATLL patients could reduce the frequency of IFN-γ producing B cells. In conclusion, these results suggest that these preparations are active, partly overlapping in their effects, and able to elicit distinct effects on target populations.

Altered structural connectivity in olfactory disfunction after mild COVID-19 using probabilistic tractography.

We aimed to investigate changes in olfactory bulb volume and brain network in the white matter (WM) in patients with persistent olfactory disfunction (OD) following COVID-19. A cross-sectional study evaluated 38 participants with OD after mild COVID-19 and 24 controls, including Sniffin' Sticks identification test (SS-16), MoCA, and brain magnetic resonance imaging. Network-Based Statistics (NBS) and graph theoretical analysis were used to explore the WM. The COVID-19 group had reduced olfactory bulb volume compared to controls. In NBS, COVID-19 patients showed increased structural connectivity in a subnetwork comprising parietal brain regions. Regarding global network topological properties, patients exhibited lower global and local efficiency and higher assortativity than controls. Concerning local network topological properties, patients had reduced local efficiency (left lateral orbital gyrus and pallidum), increased clustering (left lateral orbital gyrus), increased nodal strength (right anterior orbital gyrus), and reduced nodal strength (left amygdala). SS-16 test score was negatively correlated with clustering of whole-brain WM in the COVID-19 group. Thus, patients with OD after COVID-19 had relevant WM network dysfunction with increased connectivity in the parietal sensory cortex. Reduced integration and increased segregation are observed within olfactory-related brain areas might be due to compensatory plasticity mechanisms devoted to recovering olfactory function.

Identification of miRnas with possible prognostic roles for HAM/TSP.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropic spastic paraparesis (HAM/TSP) is an insidiously progressive spinal cord disease for which there is no effective treatment. There is great interest in developing potential biomarkers to predict the pathogenesis of HAM/TSP disease. In this study, Illumina Massive Parallel Sequencing (MPS) technology was used to investigate the cellular global noncoding RNAome expression profile in HAM/TSP patients (n = 10), asymptomatic HTLV-1-infected carriers (ASP, n = 8), and a second group of healthy controls (n = 5). Various bioinformatics tools were used to align, annotate, and profile the sRNA-MPS reads. Among the 402 sRNAs detected, 251 were known and 50 were potentially novel sRNAs in the HAM and ASP groups compared with the HC group. Sixty-eight known sRNAs were significantly different between the ASP and HAM groups. Eighty-eight mature miRNAs were downregulated in subjects from HAM compared with ASP. Three of these miRs (hsa-miR-185-5p, 32-5p, and 192-5p) have the potential to be used as biomarkers for predicting the pathogenesis of HAM/TSP. The seven most deregulated miRs target genes have been associated with a variety of biological processes and molecular functions. The reactome pathways relevant to our findings provide a rich source of data and offer the opportunity to better understand sRNA regulation and function in HTLV-1 pathophysiology. To the best of our knowledge, this study is the first to demonstrate evaluates sRNAs in HTLV-1 patients with HAM/TSP.

Small RNA Profiling in an HTLV-1-Infected Patient with Acute Adult T-Cell Leukemia-Lymphoma at Diagnosis and after Maintenance Therapy: A Case Study.

Small RNAs (sRNAs) are epigenetic regulators of essential biological processes associated with the development and progression of leukemias, including adult T-cell leukemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic human retrovirus originally discovered in a patient with adult T-cell leukemia/lymphoma. Here, we describe the sRNA profile of a 30-year-old woman with ATLL at the time of diagnosis and after maintenance therapy with the aim of correlating expression levels with response to therapy.

Neurobrucellosis Mimicking Primary CNS Vasculitis-Should We Perform CSF Metagenomics Before Brain Biopsy?: A Case Report.

Objective: To report a patient with neurobrucellosis mimicking primary CNS vasculitis (PCNSV) diagnosed by CSF metagenomic next-generation sequencing (mNGS). Methods: A 32-year-old male patient with a prior stroke developed headache, dizziness, fever, and memory complaints in the past 30 days. Physical examination was unremarkable except for slight apathy. He was investigated with brain MRI, cerebral digital angiography, CSF analysis with mNGS, and brain biopsy. Results: An examination of the brain MRI showed a left nucleocapsular gliosis compatible with prior stroke; MR angiogram showed circular enhancement of distal branches of the middle cerebral arteries. Digital angiogram revealed stenosis of intracranial carotid arteries and the left middle cerebral artery. The CSF disclosed 42 cells/mm3, 46 mg/dL of glucose, and 82 mg/dL of protein. Brain biopsy showed a chronic leptomeningeal inflammatory process, not fulfilling criteria for PCNSV. mNGS revealed the presence of Brucella sp. genetic material. He was treated with antibiotics with full remission of systemic and neurologic symptoms. Discussion: Brucellosis is an endemic disease in developing countries and may mimic PCNSV. Our patient fulfilled the criteria for possible PCNSV; however, brain biopsy was inconsistent with PCNSV, and CSF mNGS disclosed neurobrucellosis. This case illustrates the importance of CSF mNGS in the differential diagnosis of CNS vasculitis.

Neuropsychological profile of patients with infectious disease: characterization and comparison of patients with HIV, HTLV, and HCV.

Understanding the effect of the HIV, HTLV-1, and HCV viruses on cognitive aspects can help in the better characterization of dementia, as well as the best conducts to be suitable for rehabilitation. Thus, the present study aimed to characterize and compare the neuropsychological profile of 3 groups of patients with infectious diseases: HIV, HTLV, and HCV. The results of neuropsychological assessments and depression assessment of 325 people treated at a referral hospital for infectious diseases were analyzed, being 120 HIV carriers (74 (61.7%) men) with an average age of 47.5 years (SD = 10.3), 65 patients with HTLV-1 (16 (24.6%) men) with a mean age of 49.9 years (SD = 12.9), and 87 HCV patients (47 (54%) men) with a mean age of 55.5 years (SD = 11.2). In addition, 54 people (26 (48.1%) men) with negative serology who made up the control group were evaluated. The results of the statistical evaluation of the sociodemographic factors of the four groups (HIV, HTLV-1, HCV, and control) showed that in addition to age, schooling was a significant factor among them and may have a strong influence on the performance of cognitive tests. The HTLV-1 group had the lowest neurocognitive performance and also the highest rate of depressive symptoms.

Brain microstructural changes and fatigue after COVID-19.

Background: Fatigue and cognitive complaints are the most frequent persistent symptoms in patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to assess fatigue and neuropsychological performance and investigate changes in the thickness and volume of gray matter (GM) and microstructural abnormalities in the white matter (WM) in a group of patients with mild-to-moderate coronavirus disease 2019 (COVID-19). Methods: We studied 56 COVID-19 patients and 37 matched controls using magnetic resonance imaging (MRI). Cognition was assessed using Montreal Cognitive Assessment and Cambridge Neuropsychological Test Automated Battery, and fatigue was assessed using Chalder Fatigue Scale (CFQ-11). T1-weighted MRI was used to assess GM thickness and volume. Fiber-specific apparent fiber density (FD), free water index, and diffusion tensor imaging data were extracted using diffusion-weighted MRI (d-MRI). d-MRI data were correlated with clinical and cognitive measures using partial correlations and general linear modeling. Results: COVID-19 patients had mild-to-moderate acute illness (95% non-hospitalized). The average period between real-time quantitative reverse transcription polymerase chain reaction-based diagnosis and clinical/MRI assessments was 93.3 (±26.4) days. The COVID-19 group had higher total CFQ-11 scores than the control group (p < 0.001). There were no differences in neuropsychological performance between groups. The COVID-19 group had lower FD in the association, projection, and commissural tracts, but no change in GM. The corona radiata, corticospinal tract, corpus callosum, arcuate fasciculus, cingulate, fornix, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were involved. CFQ-11 scores, performance in reaction time, and visual memory tests correlated with microstructural changes in patients with COVID-19. Conclusions: Quantitative d-MRI detected changes in the WM microstructure of patients recovering from COVID-19. This study suggests a possible brain substrate underlying the symptoms caused by SARS-CoV-2 during medium- to long-term recovery.

Prevalence of cognitive impairment in HIV patients: vertical and horizontal transmission.

Antiretroviral treatment has significantly increased the survival of patients infected with HIV-1. However, with increased survival, cognitive changes associated with HIV are frequently observed in this population. The clinical manifestations of HIV changes can vary as a result of several aspects, including the virus transmission route. Several studies have pointed out premature neurological changes in vertically infected patients, while the manifestation of cognitive damage in adults may take a longer time. Objective: The aim of this study was to verify the prevalence of cognitive changes in patients with HIV via vertical transmission after the highly active antiretroviral therapy and the cognitive performance of these patients compared to a group of sexually infected patients. Methods: A total of 48 patients were evaluated, 25 with vertical transmission and 23 with sexual transmission, between May 2013 and February 2015 at the Institute of infectology Emilio Ribas. Neuropsychological tests were applied to assess cognitive performance, scales to assess symptoms of anxiety and depression, and sociodemographic questionnaire. Results: The results demonstrate that the frequency of cognitive impairment in vertically transmitted patients was higher than in sexually transmitted patients. Conclusions: These findings suggest that the deleterious effects of the HIV virus on the development of the central nervous system reverberate more strongly than in patients who acquire it after adulthood.

O tratamento antirretroviral tem aumentado significativamente a sobrevida de pacientes contaminados pelo HIV-1. Entretanto, com o aumento da sobrevida, observam-se frequentemente alterações cognitivas associadas ao HIV nessa população. As manifestações clínicas das alterações do HIV podem variar em decorrência de diversos aspectos, entre eles a via de transmissão do vírus. Diversos estudos têm apontado alterações neurológicas prematuras em pacientes contaminados por via vertical, enquanto a manifestação de danos cognitivos em adultos pode levar um tempo maior. Objetivo: O objetivo deste estudo foi verificar a prevalência das alterações cognitivas em pacientes com HIV via transmissão vertical após a era da terapia antirretroviral altamente ativa e o desempenho cognitivo desses pacientes comparado ao de um grupo de pacientes contaminados por via sexual. Métodos: Foram avaliados 48 pacientes, sendo 25 com transmissão vertical e 23 com transmissão sexual no período entre maio de 2013 e fevereiro de 2015, no Instituto de Infectologia Emílio Ribas. Foram aplicados testes neuropsicológicos para avaliar o desempenho cognitivo, escalas para avaliar sintomas de ansiedade e depressão e questionário sociodemográfico. Resultados: Os resultados demonstraram que a frequência de comprometimento cognitivo em pacientes contaminados via transmissão vertical foi maior do que naqueles contaminados via transmissão sexual. Conclusões: Essas descobertas sugerem que os efeitos deletérios do vírus HIV na formação do sistema nervoso central repercutem de forma mais acentuada do que em pacientes que o adquiriram após a vida adulta.

Subacute Cognitive Impairment in Individuals With Mild and Moderate COVID-19: A Case Series.

Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances. Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed >7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT). Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15-33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25-10.75) and altered visuospatial construction with a median of four points (IQR 4-9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-Co Conclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.

Potential autoimmune encephalitis following yellow fever vaccination: A report of three cases.

Meningoencephalitis following yellow fever vaccination is considered a viral neuroinvasive disease. We describe three patients with typical autoimmune encephalitis syndromes that developed 1-27 days following yellow fever vaccination. Anti-N-methyl-d-aspartate-r antibodies were identified in the CSF and serum of two patients and the other case was associated with anti-neurexin-3 antibodies. One case was confirmed as vaccine-associated neurotropic disease due to reactive CSF yellow fever IgM, which suggested an infectious-autoimmune overlap mechanism. Two aditional cases of Anti-N-methyl-d-aspartate-r encephalitis were identified in the literature review. Antibody-positive autoimmune encephalitis should be included in the differential diagnosis of neurologic adverse events following yellow fever vaccination.

Dichotomy in Fatal Outcomes in a Large Cohort of People Living with HTLV-1 in São Paulo, Brazil.

Background: Despite its relatively low incidence of associated diseases, Human T-cell Leukemia Virus-1 (HTLV-1) infection was reported to carry a significant risk of mortality in several endemic areas. HTLV-1-associated diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraperesis (HAM/TSP), as well as frequent coinfections with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Strongyloides stercoralis were associated to increased morbidity and mortality of HTLV-1 infection. Objective: To determine the mortality rate and its associated variables from an open cohort started in July 1997 at the HTLV Clinic, Emilio Ribas Institute (IIER), a major infectious disease hospital in São Paulo, Brazil. Methods: Since inception up to September 2018, we admitted 727 HTLV-1-infected individuals, with a rate of 30-50 new admissions per year. All patient data, including clinical and laboratory data, were regularly updated throughout the 21-year period, using a dedicated REDCap database. The Ethical Board of IIER approved the protocol. Results: During 21 years of clinical care to people living with HTLV-1 in the São Paulo region, we recruited 479 asymptomatic HTLV-1-infected individuals and 248 HAM/TSP patients, of which 632 remained under active follow-up. During a total of 3800 person-years of follow-up (maximum follow-up 21.5 years, mean follow-up 6.0 years), 27 individuals died (median age of 51.5 years), of which 12 were asymptomatic, one ATLL patient and 14 HAM/TSP patients. HAM/TSP diagnosis (but neither age nor gender) was a significant predictor of increased mortality by univariate and multivariate (hazard ratio (HR) 5.03, 95% CI [1.96-12.91], p = 0.001) Cox regression models. Coinfection with HIV/HCV was an independent predictor of increased mortality (HR 15.08; 95% CI [5.50-41.32]; p < 0.001), with AIDS-related infections as a more frequent cause of death in asymptomatics (6/13; p = 0.033). HIV/HCV-negative fatal HAM/TSP cases were all female, with urinary tract infection and decubitus ulcer-associated sepsis as the main cause of death (8/14, p = 0.002). Conclusions: All-cause mortality among people living with HTLV-1 in São Paulo differs between asymptomatic (2.9%) and HAM/TSP patients (7.3%), independent of age and gender. We observe a dichotomy in fatal cases, with HAM/TSP and HIV/HCV coinfection as independent risk factors for death. Our findings reveal an urgent need for public health actions, as the major causes of death, infections secondary to decubitus ulcers, and immune deficiency syndrome (AIDS)-related infections, can be targeted by preventive measures.

Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring.

HTLV-1 is transmitted primarily either through sexual intercourse or from mother to child. The mother/child pairs were classified as seroconcordant or serodiscordant. We analyzed mother to child transmission (MTCT) according to sociodemographic, clinical and epidemiological characteristics of the mother, child's gender and duration of breastfeeding. Between June 2006 and August 2016 we followed 192 mothers with HTLV-1 infection (mean age 41 years old), resulting in 499 exposed offspring, 288 (57.7%) of whom were tested for HTLV-1, making up the final sample for the study, along with their 134 respective mothers. Among the tested mother/child pairs, 41 (14.2%) were HTLV-1 positive, highlighted that seven of 134 family clusters concentrated 48.8% of positive cases. Variables associated with a positive child: breastfeeding duration ≥12 months, maternal PVL ≥100 copies/104 PBMC, mother's age at delivery >26 years old, and HTLV-1 in more than one child of the same mother. In a multiple logistic regression, breastfeeding ≥12 months, higher maternal PVL and ≥2 previous HTLV-1-infected children remained independently associated with the outcome. Thus, high maternal PVL and breastfeeding beyond 12 months were independently associated with MTCT of the HTLV-1 infection. Our results reinforce the need for both prenatal HTLV screening in endemic areas and for advising mothers on breastfeeding.

Neuropsychological Assessment of 412 HIV-Infected Individuals in São Paulo, Brazil.

HIV-associated neurocognitive disorders (HAND) remain frequent even among individuals receiving combined antiretroviral therapy (cART). In addition, HAND may adversely affect the quality of life and adherence to cART. There is scarce epidemiological information about HAND in Latin America. This cross-sectional study recruited HIV-infected patients from a tertiary teaching institution in São Paulo, Brazil, between May 2013 and February 2015. The patients were adults with at least 4 years of education and patients with current neurological or psychiatric diseases were excluded. HAND remain frequent even among individuals receiving cART, use of psychoactive substance, or inability to understand the content for neuropsychological evaluation. We used standardized tools to evaluate depression, use of psychoactive substances, and daily life activities, and we performed a comprehensive neuropsychological examination. HAND was classified using the Frascati criteria. Prevalence of HAND was estimated, and an associated variable of symptomatic HAND was identified by logistic regression. Four-hundred twelve HIV-infected patients were included [male: 281 (68%), mean age of 45.3 years]. Most of them [n = 340 (83.7%)] had an undetectable viral load. The prevalence of HAND was 73.6% (n = 303): 210 (50.9%) had asymptomatic neurocognitive involvement (ANI), 67 (16.2%) had mild neurocognitive disorder (MND), and 26 (6.3%) had HIV-associated dementia (HAD). The univariate logistic regression analysis showed that female gender, age older than 50 years, <11 years of schooling, CD4 count below 200 cells/mm3, presence of previous illnesses (e.g., diabetes, hypertension), opportunistic disease history, and a Beck Depression Inventory (BDI) score between 13 and 19 points were factors associated with symptomatic HAND (MND and HAD). However, a BDI score between 13 and 19 points was the single independent variable associated with symptomatic HAND. HAND was highly prevalent in São Paulo, Brazil, and ANI was the more frequent category of HAND. However, 22.5% of participants had symptomatic HAND. This finding constitutes a challenge in clinical practice. A BDI score between 13 and 19 points was the single independent variable associated with symptomatic HAND.

Polymorphisms in HLA-C and KIR alleles are not associated with HAM/TSP risk in HTLV-1-infected subjects.

INTRODUCTION: Several genetic polymorphisms may be related to susceptibility or resistance to viral disease outcomes. Immunological or genetic factors may act as major triggers of the immune pathogenesis of HAM/TSP. This study investigated the association of immune related genetic polymorphisms with viral and immunological markers. METHODS: 247 HTLV-1-infected volunteers, drawn from a larger group of HTLV-infected subjects followed at the Institute of Infectious Diseases "Emilio Ribas" (IIER) for up to 19 years, participated in this study, which ran from June 2011 to July 2016. The subjects were classified according to their neurological status into two groups: Group 1 (160 asymptomatic individuals) and Group 2 (87 HAM/TSP patients). Samples were tested for spontaneous lymphocyte proliferation (LPA) and HTLV-1 proviral load (PVL) and for IFN-λ4, HLA-C and KIR genotypes using qPCR. RESULTS: We found associations between LPA (p=0.0001) with HAM/TSP and confirmed the IFN-λ4 polymorphism rs8099917, allele GG, as a protective factor using a recessive model (OR=3.22, CI=1.10-9.47). Polymorphisms in HLA-C and KIR alleles were not associated with risk of developing HAM/TSP. CONCLUSION: We demonstrated that age, LPA and an IFN-λ4 polymorphism were associated with progression to HAM/TSP. Understanding HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management, and contribute to the discovery of new therapeutic interventions in the future.

Human parvovirus 4 prevalence among HTLV-1/2 infected individuals in Brazil.

Human parvovirus 4 (PARV4), a Tetraparvovirus, has been largely found in HIV, HBV, or HCV infected individuals. However, there is no data for the PARV4 occurrence in Human T-lymphotropic virus (HTLV-1/2) infected individuals, despite similar transmission routes. Here, PARV4 viremia was evaluated in 130 HTLV infected patients under care of a Brazilian HTLV outpatient clinic. PARV4 viremia was detected in 6.2% of the HTLV-1 infected patients. Most PARV4 positives showed no evidence for parenterally transmitted infections. It is suggested that in Brazil, transmission routes of PARV4 are more complex than in Europe and North America and resemble those in Africa. J. Med. Virol. 89:748-752, 2017. © 2016 Wiley Periodicals, Inc.