IL-10 predicts incident neuroinflammatory disease and proviral load dynamics in a large Brazilian cohort of people living with human T-lymphotropic virus type 1.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

Postorotracheal intubation dysphagia in patients with COVID-19: A retrospective study.

BACKGROUND: The cause of oropharyngeal dysphagia in patients with coronavirus disease (COVID-19) can be multifactorial and may underly limitations in swallowing rehabilitation. OBJECTIVE: Analyze the factors related to dysphagia in patients with COVID-19 immediately after orotracheal extubation and the factors that influence swallowing rehabilitation. DESIGN AND SETTING: A retrospective study. METHODS: The presence of dysphagia was evaluated using the American Speech-Language Hearing Association National Outcome Measurement System (ASHA NOMS) scale and variables that influenced swallowing rehabilitation in 140 adult patients who required invasive mechanical ventilation for >48 h. RESULTS: In total, 46.43% of the patients scored 1 or 2 on the ASHA NOMS (severe dysphagia) and 39.29% scored 4 (single consistency delivered orally) or 5 (exclusive oral diet with adaptations). Both the length of mechanical ventilation and the presence of neurological disorders were associated with lower ASHA NOMS scores (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.74-0.87 P < 0.05; and OR: 0.13, 95% CI: 0.61-0.29; P < 0.05, respectively). Age and the presence of tracheostomy were negatively associated with speech rehabilitation (OR: 0.92; 95% CI: 0.87--0.96; OR: 0.24; 95% CI: 0.80--0.75), and acute post-COVID-19 kidney injury requiring dialysis and lower scores on the ASHA NOMS were associated with longer time for speech therapy outcomes (ß: 1.62, 95% CI, 0.70-3.17, P < 0.001; ß: -1.24, 95% CI: -1.55--0.92; P < 0.001). CONCLUSION: Prolonged orotracheal intubation and post-COVID-19 neurological alterations increase the probability of dysphagia immediately after extubation. Increased age and tracheostomy limited rehabilitation.

HTLV-1-Associated Myelopathy (HAM) Incidence in Asymptomatic Carriers and Intermediate Syndrome (IS) Patients.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

Postorotracheal intubation dysphagia in patients with COVID-19: A retrospective study

ABSTRACT BACKGROUND: The cause of oropharyngeal dysphagia in patients with coronavirus disease (COVID-19) can be multifactorial and may underly limitations in swallowing rehabilitation. OBJECTIVE: Analyze the factors related to dysphagia in patients with COVID-19 immediately after orotracheal extubation and the factors that influence swallowing rehabilitation. DESIGN AND SETTING: A retrospective study. METHODS: The presence of dysphagia was evaluated using the American Speech-Language Hearing Association National Outcome Measurement System (ASHA NOMS) scale and variables that influenced swallowing rehabilitation in 140 adult patients who required invasive mechanical ventilation for >48 h. RESULTS: In total, 46.43% of the patients scored 1 or 2 on the ASHA NOMS (severe dysphagia) and 39.29% scored 4 (single consistency delivered orally) or 5 (exclusive oral diet with adaptations). Both the length of mechanical ventilation and the presence of neurological disorders were associated with lower ASHA NOMS scores (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.74-0.87 P < 0.05; and OR: 0.13, 95% CI: 0.61-0.29; P < 0.05, respectively). Age and the presence of tracheostomy were negatively associated with speech rehabilitation (OR: 0.92; 95% CI: 0.87-−0.96; OR: 0.24; 95% CI: 0.80-−0.75), and acute post-COVID-19 kidney injury requiring dialysis and lower scores on the ASHA NOMS were associated with longer time for speech therapy outcomes (β: 1.62, 95% CI, 0.70-3.17, P < 0.001; β: −1.24, 95% CI: −1.55-−0.92; P < 0.001). CONCLUSION: Prolonged orotracheal intubation and post-COVID-19 neurological alterations increase the probability of dysphagia immediately after extubation. Increased age and tracheostomy limited rehabilitation.

Acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome: prevalence, main characteristics, and outcomes in a Brazilian center.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) - immune reconstitution inflammatory syndrome (IRIS) in people living with HIV/AIDS (PLWHA) has been rarely described in low- and middle-income countries. OBJECTIVE: To describe the prevalence of PML-IRIS among PLWHA with PML and its main features in a tertiary hospital in Brazil. METHODS: We performed a retrospective cohort study. We included PLWHA with PML-IRIS patients admitted at Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, between 2011 and 2021. We retrieved information on neurological manifestations, neuroimaging findings, treatments, and outcomes. RESULTS: We identified 11 (11.8%) PML-IRIS cases among 93 patients with definite PML. Eight (73%) cases were men and had a median (IQR) age of 41 (27-50) years. Seven (63.6%) patients developed unmasking PML-IRIS and 4 (36.4%) had paradoxical PML-IRIS. The median (IQR) time from initiation of combined antiretroviral therapy (cART) to IRIS diagnosis was 49 (30-70) days. Ten (90.9%) patients received corticosteroids. There were 4 (36%) in-hospital deaths and 3 were associated with hospital-acquired pneumonia. Among the 7 (64%) patients who survived, 5 (71.5%) had sequelae at discharge. One year after the PML-IRIS diagnosis, 6 (54.5%) patients were alive. CONCLUSION: The prevalence of PML-IRIS was 11.8%. Most patients had unmasking PML-IRIS. In-hospital mortality and morbidity were high. One-year survival was similar to that described in some high-income countries.

ANTECEDENTES: A síndrome inflamatória de reconstituição imune (SIRI) da leucoencefalopatia multifocal progressiva (LEMP) em pessoas vivendo com HIV/Aids (PVHA) foi raramente descrita em países de baixa e média renda. OBJETIVO: Descrever a prevalência da SIRI-LEMP- em PVHA com LEMP e suas principais características em um hospital no Brasil. MéTODOS: Foi realizado um estudo de coorte retrospectivo. Incluímos PVHA com SIRI-LEMP admitidos no Instituto de Infectologia Emílio Ribas, São Paulo, Brasil, entre 2011 e 2021. Recuperamos informações sobre manifestações neurológicas, neuroimagem, tratamento e desfecho. RESULTADOS: Identificamos 11 (11,8%) casos de SIRI-LEMP entre 93 pacientes com LEMP definitiva. Oito (73%) casos eram homens e a mediana de idade (amplitude interquartile - AIQ) foi de 41 (27­50) anos. Sete (63,6%) pacientes desenvolveram SIRI-LEMP "desmascarada" e 4 (36,4%) casos apresentaram SIRI-LEMP "paradoxal". A mediana de tempo (AIQ) desde o início da terapia antirretroviral combinada (cART) até o diagnóstico de SIRI foi de 49 (30­70) dias. Dez (90,9%) pacientes receberam corticoide. Houve 4 (36%) óbitos intra-hospitalares e 3 foram associados à pneumonia hospitalar. Dos 7 (64%) pacientes que sobreviveram, 5 (71,5%) ficaram com sequelas na alta. Um ano após o diagnóstico de SIRI-LEMP, 6 (54,5%) pacientes estavam vivos. CONCLUSãO: A prevalência de SIRI-LEMP foi de 11,8%. A maioria dos pacientes apresentava SIRI-LEMP "desmascarada". A mortalidade e morbidade hospitalar foram altas. A sobrevida em 1 ano foi semelhante à descrita em alguns países de alta renda.

High prevalence of central nervous system cryptococcosis using a fingerprick whole-blood lateral flow assay in individuals with neurological symptoms and advanced HIV disease in a Brazilian emergency department.

Timely diagnosis is key in managing central nervous system (CNS) cryptococcosis in people living with HIV/AIDS (PLWHA). There are few data on implementing fingerprick whole-blood cryptococcal antigen (CrAg) lateral flow assay (LFA) as the first test for diagnosing CNS cryptococcosis. We evaluated the prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood in a referral emergency department (ED) in São Paulo, Brazil. This was a prospective cohort study of consecutive adult PLWHA with advanced HIV disease and neurological symptoms. Fingerprick whole-blood CrAg LFA was performed at bedside. Seventy-four individuals were enrolled (median age = 40 years; males = 62%). Prevalence of CNS cryptococcosis was 17.6% (13/74); 95% confidence interval (CI), 9.4-30.0%, and prevalence of positive fingerprick whole-blood CrAg LFA was 25.7% (19/74); 95% CI, 15.5-40.1%. Among the six (8.1%) patients with positive fingerprick whole-blood CrAg LFA and negative CSF CrAg LFA, four (5.4%) had isolated asymptomatic cryptococcal antigenemia, one (1.3%) had symptomatic cryptococcal antigenemia, and one (1.3%) had cryptococcemia. Prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood CrAg LFA was high. Point-of-care testing was important for diagnosing CNS cryptococcosis in an ED from a middle-income country.

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.

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.

Could Cesarean Delivery Help Prevent Mother-to-Child Transmission of Human T-Lymphotropic Virus Type 1?

BACKGROUND: Mother-to-child transmission (MTCT) of human T-lymphotropic virus type 1 (HTLV-1) is an important route of transmission that can cause lifelong infection. There is high morbidity and mortality due to adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy (HAM), and other inflammatory disorders. These conditions develop in nearly 10% of people with HTLV-1 infection, with a higher risk if infection occurs early in life. Identification of risk factors can inform targeted measures to reduce HTLV-1 MTCT. This study aimed to investigate the potential of cesarean delivery to prevent HTLV-1 MTCT. METHODS: We performed a review of the cases of women and their offspring under regular follow-up at the HTLV-1 outpatient clinic at the Institute of Infectious Diseases Emilio Ribas. RESULTS: A total of 177 HTLV-1-infected women and 369 adult offspring were investigated. Overall, 15% of the children were positive for HTLV-1 and 85% were negative. Regarding vertical transmission, we found that a breastfeeding duration of >6 months was associated with MTCT. Moreover, maternal proviral load was not associated with transmission, but high educational level and cesarean delivery were identified as protective factors. CONCLUSIONS: HTLV-1 MTCT was associated with mother's age at delivery of >25 years, low educational level, prolonged breastfeeding, and vaginal delivery.

Cytomegalovirus retinitis in hospitalized people living with HIV in the late antiretroviral therapy era in São Paulo, Brazil.

BACKGROUND: There is scarce information on AIDS-related cytomegalovirus (CMV) retinitis in middle-income countries. The objectives of this study were to identify the prevalence of active CMV retinitis in severely immunosuppressed people living with HIV (PLWHIV) and to describe its main features. METHODS: This retrospective cohort study was carried out at a tertiary center in São Paulo, Brazil. We included hospitalized adults PLWHIV with CD4 count ≤100 cells/µL, ≥ one quantitation of CMV DNA in plasma, and indirect ophthalmoscopy evaluation. RESULTS: Thirty-eight (21.6%) of 176 participants had at least an ophthalmoscopy diagnosis and only 3 (1.7%) individuals presented active CMV retinitis. All these participants were male, and retinitis was asymptomatic in 2 cases. Two participants had extraocular end-organ CMV disease and detectable CMV DNA in plasma. CONCLUSIONS: These results show a low prevalence of active CMV retinitis in the evaluated population. However, 2 of 3 participants had asymptomatic active CMV retinitis and a fifth of participants had at least one ophthalmoscopy diagnosis, suggesting the need for routine ophthalmologic evaluation in hospitalized severely immunosuppressed PLWHIV. The profile of participants with active CMV retinitis was similar to that described in the pre-ART era and quantitation of CMV DNA in plasma was variable.

CCR5-∆32, CCR2-64I, SDF1-3'A, and IFNλ4 rs12979860 and rs8099917 gene polymorphisms in individuals with HIV-1, HIV/HTLV-1, and HIV/HTLV-2 in São Paulo, Brazil

Background. Chemokine and chemokine-receptor polymorphisms have been associated with protection against HIV infection and delayed progression to AIDS, whereas polymorphisms in IFNλ4 (formerly IL28B) have been associated with human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy (HAM) development. Evolutionary selection against ancestral genes differs among human populations, resulting in varying risks of acquiring and developing viral diseases. Methods. DNA samples from 434 patients infected with HIV-1 and/or co-infected with HTLV-1/-2, and samples from 74 HIV and HTLV non-infected individuals from São Paulo, Brazil, were divided into five groups: HIV-naïve, n=160; HIV-ART, n=180; HIV/HTLV-1, n=53; HIV/HTLV-2, n=41; and control, n=74. These samples were analyzed for CCR5-∆32deletion, CCR2-64I, SDF1-3'A, and IFNλ4 rs12979860 and rs8099917 single nucleotide polymorphisms using PCR and PCR-RFLP techniques. These polymorphisms' genotype and allele frequencies were calculated and compared among groups using logistic regression analysis. Results. All polymorphism profiles described in the literature were detected in this study. The wild-type genotype predominated in all genes analyzed except for IFNλ4 rs12979860. Statistical differences in allele frequencies among groups were detected in the CCR5 and CCR2 genes, with a high frequency of ∆32 in HIV-naïve vs. HIV-ART (OR 2.45, P=0.037) and a minus mutant allele A (CCR2-64I) in HIV-naïve vs. HIV/HTLV-1 (OR 1.90, P=0.048), HIV-ART vs. HIV/HTLV-1 (OR 2.62, P=0.003), and HIV/ART vs. HIV/HTLV-2 (OR 2.42, P=0.016). Conclusions. The polymorphism profiles detected in the study groups corroborate the profiles described in racial admixed populations. High CCR2-64I mutant allele frequencies were detected in HIV/HTLV-1/-2 co-infected individuals, and CCR5-∆32 showed predictive value for ART initiation. (AU)

Acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome: prevalence, main characteristics, and outcomes in a Brazilian center / Síndrome inflamatória de reconstituição imune da leucoencefalopatia multifocal progressiva associada à síndrome da imunodeficiência adquirida: prevalência, principais características e desfecho em um hospital brasileiro

Abstract Background Progressive multifocal leukoencephalopathy (PML) - immune reconstitution inflammatory syndrome (IRIS) in people living with HIV/AIDS (PLWHA) has been rarely described in low- and middle-income countries. Objective To describe the prevalence of PML-IRIS among PLWHA with PML and its main features in a tertiary hospital in Brazil. Methods We performed a retrospective cohort study. We included PLWHA with PML-IRIS patients admitted at Instituto de Infectologia Emílio Ribas, São Paulo, Brazil, between 2011 and 2021. We retrieved information on neurological manifestations, neuroimaging findings, treatments, and outcomes. Results We identified 11 (11.8%) PML-IRIS cases among 93 patients with definite PML. Eight (73%) cases were men and had a median (IQR) age of 41 (27-50) years. Seven (63.6%) patients developed unmasking PML-IRIS and 4 (36.4%) had paradoxical PML-IRIS. The median (IQR) time from initiation of combined antiretroviral therapy (cART) to IRIS diagnosis was 49 (30-70) days. Ten (90.9%) patients received corticosteroids. There were 4 (36%) in-hospital deaths and 3 were associated with hospital-acquired pneumonia. Among the 7 (64%) patients who survived, 5 (71.5%) had sequelae at discharge. One year after the PML-IRIS diagnosis, 6 (54.5%) patients were alive. Conclusion The prevalence of PML-IRIS was 11.8%. Most patients had unmasking PML-IRIS. In-hospital mortality and morbidity were high. One-year survival was similar to that described in some high-income countries.

Resumo Antecedentes A síndrome inflamatória de reconstituição imune (SIRI) da leucoencefalopatia multifocal progressiva (LEMP) em pessoas vivendo com HIV/Aids (PVHA) foi raramente descrita em países de baixa e média renda. Objetivo Descrever a prevalência da SIRI-LEMP- em PVHA com LEMP e suas principais características em um hospital no Brasil. Métodos Foi realizado um estudo de coorte retrospectivo. Incluímos PVHA com SIRI-LEMP admitidos no Instituto de Infectologia Emílio Ribas, São Paulo, Brasil, entre 2011 e 2021. Recuperamos informações sobre manifestações neurológicas, neuroimagem, tratamento e desfecho. Resultados Identificamos 11 (11,8%) casos de SIRI-LEMP entre 93 pacientes com LEMP definitiva. Oito (73%) casos eram homens e a mediana de idade (amplitude interquartile - AIQ) foi de 41 (27-50) anos. Sete (63,6%) pacientes desenvolveram SIRI-LEMP "desmascarada" e 4 (36,4%) casos apresentaram SIRI-LEMP "paradoxal". A mediana de tempo (AIQ) desde o início da terapia antirretroviral combinada (cART) até o diagnóstico de SIRI foi de 49 (30-70) dias. Dez (90,9%) pacientes receberam corticoide. Houve 4 (36%) óbitos intra-hospitalares e 3 foram associados à pneumonia hospitalar. Dos 7 (64%) pacientes que sobreviveram, 5 (71,5%) ficaram com sequelas na alta. Um ano após o diagnóstico de SIRI-LEMP, 6 (54,5%) pacientes estavam vivos. Conclusão A prevalência de SIRI-LEMP foi de 11,8%. A maioria dos pacientes apresentava SIRI-LEMP "desmascarada". A mortalidade e morbidade hospitalar foram altas. A sobrevida em 1 ano foi semelhante à descrita em alguns países de alta renda.

Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Neurological manifestations in people living with HIV/AIDS in the late cART era: a prospective observational study at a tertiary healthcare center in São Paulo, Brazil.

Background:The aim of this study was to evaluate the frequency, spectrum, in-hospital mortality rate, and factors associated with death in people living with HIV/AIDS (PLWHA) presenting with neurological diseases from a middle-income country, as well as estimate its one-year global death rate.Methods:This prospective observational cohort study was conducted at a Brazilian tertiary health center between January and July 2017. HIV-infected patients above 18 years of age who were admitted due to neurological complaints were consecutively included. A standardized neurological examination and patient and/or medical assistant interviews were performed weekly until the patient's discharge or death. The diagnostic and therapeutic management of the included cases followed institutional routines.Results:A total of 105 (13.2%) patients were included among the 791 hospitalized PLWHA. The median age was 42.8 [34-51] years, and 61% were men. The median CD4+ lymphocyte cell count was 70 (27-160) cells/mm3, and 90% of patients were experienced in combined antiretroviral therapy. The main diseases were cerebral toxoplasmosis (36%), cryptococcal meningitis (14%), and tuberculous meningitis (8%). Cytomegalovirus causing encephalitis, polyradiculopathy, and/or retinitis was the third most frequent pathogen (12%). Moreover, concomitant neurological infections occurred in 14% of the patients, and immune reconstitution inflammatory syndrome-related diseases occurred in 6% of them. In-hospital mortality rate was 12%, and multivariate analysis showed that altered level of consciousness (P = 0.04; OR: 22.7, CI 95%: 2.6-195.1) and intensive care unit (ICU) admission (P = 0.014; OR: 6.2, CI 95%: 1.4-26.7) were associated with death. The one-year global mortality rate was 31%.Conclusion:In this study, opportunistic neurological diseases were predominant. Cytomegalovirus was a frequent etiological agent, and neurological concomitant diseases were common. ICU admission and altered levels of consciousness were associated with death. Although in-hospital mortality was relatively low, the one-year global death rate was higher.

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.

Combining urine antigen and blood polymerase chain reaction for the diagnosis of disseminated histoplasmosis in hospitalized patients with advanced HIV disease.

Disseminated histoplasmosis (DH) is endemic in Latin America and the Caribbean where diagnostic tools are restricted. We carried-out a 1-year prospective cohort study at a referral hospital in São Paulo, Brazil. Participants had > or =18 years old, were hospitalized due to any indication and had CD4+ < 200 cells/µl. A urine commercial monoclonal Histoplasma galactomannan enzyme-linked immunosorbent assay (IMMY, Norman, OK, USA) and 'in house' Histoplasma blood nested PCR were performed in all cases. Probable/proven DH cases were defined according to international guidelines. Conventional mycological methods were available in routine conditions to investigate suspected DH cases. Treatment of participants followed the institutional routine. One-hundred six participants were included. Median age (interquartile range [IQR]) was 39.5 years (30.0-47.3) and 80 individuals (75.5%) were males. Median (IQR) CD4 cell count was 26.5 (9.4-89.3) cells/mm3. DH was diagnosed in 8/106 patients (7.5%). Antigen assay and/or PCR were positive in 4.7% (5/106) of patients. The antigen assay and/or PCR identified 37.5% (3/8) of DH cases, which had not been diagnosed with conventional mycological methods, but had clinical manifestations compatible with HD. In conclusion, the use of Histoplasma urine antigen and Histoplasma blood PCR guided by CD4 status contributed to the diagnosis of DH in hospitalized individuals. These assays were complementary to conventional mycologic methods and are urgently needed in our setting. LAY SUMMARY: In this prospective cohort study carried-out in a referral center in São Paulo, Brazil, we found a high frequency of AIDS-related disseminated histoplasmosis (8/106, 7.5%). We used urine antigen test and blood PCR assay to improve the diagnosis of this opportunistic disease.

Small cells lung epidermoid carcinoma in a HTLV1-infected patient: case report and literature review.

The human T cell lymphotropic virus type 1 (HTLV-1) is the first human retrovirus discovered. Since then, it has spread worldwide and is mainly associated with adult T cell leukemia/lymphoma (ATLL) and HTLV1-associated myelopathy (HAM). Its relationship, however, with other types of cancer is controversial. We describe the case of a patient presenting with small cells lung epidermoid carcinoma who had recently developed HAM, and a review of the literature related to these conditions. This is the first case of this type of lung cancer, the same of the first description in the literature, associated with HAM outside Japan.

HIV-Associated Cryptococcal Meningitis Patients Treated with Amphotericin B Deoxycholate Plus Flucytosine under Routine Care Conditions in a Referral Center in São Paulo, Brazil.

BACKGROUND: Cryptococcal meningitis remains a common cause of mortality in low- and middle-income countries, where amphotericin B deoxycholate (amphotericin) plus fluconazole is the most common treatment. Flucytosine is almost uniformly absent as is outcome data on flucytosine use in routine care. The main goal of this study was identified the cumulative mortality at 2, 4, and 10 weeks after hospital admission. METHODS: We conducted a retrospective, observational cohort study among HIV-infected adults with cryptococcal meningitis receiving amphotericin plus flucytosine as induction therapy in Brazil. We assessed cumulative mortality at 2, 4, and 10 weeks and the cumulative proportion discontinuating amphotericin or flucytosine due to toxicity at 2 weeks. We performed multiple logistic regression to identify variables associated with in-hospital mortality. RESULTS: In total, 77 individuals (n = 66 men) were included with median baseline CD4 of 29 (IQR, 9-68) cells/mcL. Twenty (26%) had at least one concurrent neurological disease diagnosed. Sixty (78%) patients received at least 14 days of amphotericin plus flucytosine. Cumulative mortality was 5% (4/77) at 2 weeks, 8% (6/77) at 4 weeks, and 19% (15/77) at 10 weeks. Cumulative proportion of patients that discontinuated amphotericin or flucytosine due to toxicity was 20% (16/77) at 2 weeks. In addition, in-hospital mortality was associated with receiving ≤ 10 days of induction therapy (odds ratio = 4.5, 95% CI 1.2-17.1, P = 0.028) or positive cerebrospinal fluid fungal culture after 2 weeks (odds ratio = 3.8, 95% CI 1.1-13.5, P = 0.035). CONCLUSION: In this "real-world" study, amphotericin plus flucytosine shows low early mortality of patients with HIV-associated cryptococcal meningitis. Early discontinuation due to adverse events was moderate. More effective and safe antifungals are needed in order to improve the outcome of cryptococcal meningitis.