Results of a sample-to-cutoff ratio using Abbott Architect rHTLV-I/II assay allow to predict detection of HTLV-1 and HTLV-2 proviral DNA by real-time PCR / Resultados da razão sinal da amostra sobre o cutoff da reação no ensaio Abbott Architect rHTLV-I/II permite prever a detecção de DNA proviral por PCR em tempo real

The present study aims to correlate the sample-to-cutoff ratios (S/CO) distributions of reactive results for HTLV-1/2 antibodies with the detection of proviral DNA in a population of blood donor candidates. It was carried out a retrospective data search of 632 HTLV-1/2 reactive samples, submitted to confirmatory testing from January 2015 to December 2019. Serological screening was performed by chemiluminescent microparticle immunoassay Architect rHTLV-I/II, whereas confirmatory testing was performed by in-house real-time polymerase chain reaction method. 496 out of 632 samples (78%) had undetectable HTLV-1/2 proviral DNA and 136 (22%) had detectable proviral DNA. HTLV infection was not confirmed in any individual for whom the S/CO ratio value was <4, and proviral DNA detection rates gradually escalated as S/CO ratio values increased. The sensitivity and predictive positive value found for the Architect rHTLV-I/II was 100% and 22%, respectively. The receiver operating characteristic (ROC) curve analysis showed that the optimal S/CO ratio value for predicting the presence of HTLV-1/2 was 18.11. High S/CO ratios were more associated with the detection of proviral DNA. The S/CO ratio value <4 suggests excluding true HTLV infection and the risk of blood transmission (AU).

O estudo tem como objetivo correlacionar às distribuições das razões sample-to-cutoff (S/CO) de resultados reagentes para anticorpos HTLV-1/2 com a detecção de DNA proviral em uma população de candidatos à doação de sangue. Realizou-se uma busca retrospectiva de dados de 632 amostras reagentes para HTLV-1/2 submetidas à testagem confirmatória entre janeiro de 2015 a dezembro de 2019. A triagem sorológica foi realizada pelo imunoensaio quimioluminescente de micropartículas Architect rHTLV-I/II, enquanto o teste confirmatório foi realizado pelo método de PCR em tempo real in-house. 496 de 632 amostras (78%) apresentaram DNA proviral indetectável e 136 (22%) apresentaram DNA proviral detectável. A infecção por HTLV não foi confirmada em nenhum indivíduo com valor de S/CO <4 e as taxas de detecção de DNA proviral escalonaram gradualmente à medida que as razões S/CO aumentaram. A sensibilidade e valor preditivo positivo encontrados para o Architect rHTLV-I/II foram 100% e 22%, respectivamente. Utilizando análise de curva ROC, o valor de razão S/CO ideal para predizer a presença de DNA proviral foi de 18,11. Razões S/CO elevadas foram mais associadas à detecção de DNA proviral. Em suma, o valor de S/CO <4 sugere a exclusão de infecção por HTLV e o risco de transmissão pelo sangue (AU).

Clinical profile of human T-lymphotropic virus type I: a forgotten infection in pediatrics / Perfil clínico del virus linfotrópico humano tipo I: una infección olvidada en pediatría

Summary The Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus with oncogenic properties, affects around ten to twenty million people worldwide. The most common disorders associated with HTLV-1 infection are T-cell leukemia/lymphoma (ALT) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Studies have reported other clinical manifestations in HTLV-1 seropositive patients, including inflammatory disorders, co-infections with opportunistic agents, and pulmonary diseases. Objective: Here, we aim to describe a cohort of juvenile patients with confirmed HTLV-1 infection that showed clinical manifestations other than neurological symptoms. Methodology and patients: Retrospective analysis of clinical data describing background and clinical findings of 12 juvenile patients with confirmed HTLV-1 infection, attended during January 2018 to February 2020 in a pediatric referral hospital in Cali, Colombia. Results: 11 out 12 patients were from Colombia´s Pacific coast, 10 suffered from significant nutritional deficiencies. Six exhibited dermatological findings, 3 compatible with infective dermatitis. None of the cases exhibited clinical or laboratory findings suggesting ALT or HAM/TPS. Eight patients had structural lung disease assessed by chest Computed Tomography (CT) scans; 4 of them tested positive for galactomannan antigen in bronchoalveolar fluid suggesting pulmonary aspergillosis, and 2 others exhibited a positive PCR testing for tuberculosis. Three patients were diagnosed with autoimmune disorders; 1 patient with Crohn´s Diseases, 1 case of autoimmune thrombocytopenic purpura, and a patient with Vogt-Koyanagi-Harada syndrome (non-granulomatous uveitis). Conclusions: There is a broad range of clinical manifestations in pediatric HTLV-1 patients, and the clinician should consider structural pulmonary disease, opportunistic co-infections and autoimmune disorders in the diagnostic algorithm.

Resumen El Virus Linfotrópico de células T humanas tipo 1 (HTLV-1), retrovirus con propiedades oncogénicas, afecta alrededor de 10-20 millones de personas mundialmente. Las manifestaciónes más comúnmente asociadas a HTLV-1 incluyen leucemia/linfoma de células T (ALT) y mielopatía asociada a HTLV-1/ paraparesia espástica tropical (HAM/TSP). Estudios han reportado otras manifestaciones clínicas en pacientes positivos para HTLV-1, incluyendo enfermedades inflamatorias, coinfecciones con gérmenes oportunistas y enfermedad pulmonar. Objetivo: es describir clínicamente una cohorte de pacientes pediátricos con infección por HTLV-1 confirmada que presentan manifestaciones clínicas diferentes a síntomas neurológicos. Metogolodía y pacientes: Análisis retrospectivo de historia clínica describiendo procedencia y hallazgos clínicos en 12 pacientes con infección por HTLV-1 confirmada, atendidos durante el periodo de Enero de 2018 a Febrero de 2020 en un hospital pediátrico de referencia en Cali, Colombia. Resultados: Once de 12 pacientes procedían de la costa Pacífica Colombiana, 10 con deficiencias nutricionales significativas. Seis mostraron compromiso dermatológico, 3 compatibles con dermatitis infectiva. Ningún paciente presentó hallazgos clínicos o paraclínicos sugestivos de ALT o HAM/TPS. Ocho pacientes presentaron enfermedad pulmonar estructural evidenciada por TAC de tórax; 4 de ellos con antígeno galactomanan positivo en lavado broncoalveolar, sugiriendo aspergilosis pulmonar, y otros 2 resultaron con PCR positiva para tuberculosis. Tres pacientes presentaron enfermedades autoinmunes concomitantes: uno con Enfermedad de Crohn, uno con Púrpura Trombocitopénica Autoinmune, y un paciente con Síndrome de Vogt-Koyanagi-Harada. Conclusiones: Existe un amplio rango de manifestaciones clínicas en pacientes pediátricos con HTLV-1, considerando enfermedad pulmonar estructural, coinfecciones oportunistas y enfermedades autoinmunes dentro del algoritmo diagnóstico.

Intrinsic and Extrinsic Cell Apoptotic Pathways in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Systematic Review.

We aimed to verify the influence of intrinsic and extrinsic cell apoptotic pathways on the inhibition of cellular apoptosis in patients with tropical spastic paralysis/myelopathy related to human T cell lymphotropic virus type 1. The databases accessed were PubMed, Scopus, Science Direct, and Web of Science. Neither the time of publishing nor the language of the articles was limited. The descriptors used for this systematic literature review were: Tropical Paraparesis, Proto-Oncogenic Protein C, Bcl-2, Bcl-X Protein, Bax protein, Fas ligand (FasL) protein, Fas receptor, TNF-related apoptosis-inducing ligand and Fas-associated protein with death domain (FADD)-like apoptosis regulating. The search resulted in 546 articles from which 9 articles were selected for analysis; ranging from serum levels of Bcl-2, Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) measured by enzyme-linked immunosorbent assay and the levels of cellular expression of Bcl-2 and Bcl-xL the TCD4+ lymphocytes accessed by western blot. Most studies accessed either gene expression or polymorphism of Fas, FasL, and TRAIL in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas one study used flow cytometry and fluorescence to determine Fas expression. Increased Bcl-xL expression inhibited T lymphocyte apoptosis, whereas Bcl-2, serum levels, and cellular expression did not influence T lymphocyte apoptosis and serum levels of Fas were significantly higher and associated with markers of leukocyte activation in patients with HAM/TSP. In addition, Fas polymorphism (FAS-670AA) was associated with higher proviral load. There is a need for additional research on this issue since the number of patients was small and the studies presented higher heterogeneity.

Avaliação comportamental e eletrofisiológica do Processamento Auditivo Central na detecção de alterações subclínicas e comprometimento cognitivo em indivíduos infectados pelo HTLV-1 / Behavioral and electrophysiological evaluation of Central Auditory Processing in the detection of subclinical changes and cognitive impairment in individuals infected by HTLV-1

Introdução: A infecção pelo vírus linfotrópico humano de células T do tipo 1 (HTLV -1) possui um amplo espectro de manifestações clínicas, dentre as quais se destaca a mielopatia associada ao HTLV-1/paraparesia tropical espástica (HAM/TSP). Novas perspectivas diagnósticas, como a avaliação do processamento auditivo central (PAC) podem auxiliar na identificação precoce de alterações subclínicas e comprometimento cognitivo no curso da infecção pelo HTLV-1. Objetivo: avaliar as respostas comportamentais e eletrofisiológicas do PAC na infecção pelo HTLV-1 e correlacioná-las à autopercepção da memória do dia a dia. Metodologia: Estudo comparativo transversal aninhado a uma coorte de ex-doadores de sangue infectados pelo HTLV-1 e controles não infectados pareados por idade, sexo e escolaridade. A autopercepção da memória para o dia a dia foi obtida por pontuação de zero a 10 em escala visual. O PAC foi avaliado por testes auditivos comportamentais com tarefas de escuta dicótica, fala monoaural de baixa redundância, ordenação temporal, resolução temporal e interação binaural, e pelo potencial evocado cognitivo (P300). Resultados: Participaram 15 indivíduos infectados HAM/TSP, 20 infectados assintomáticos e 35 controles soronegativos saudáveis. A latência do P300 e o escore de autopercepção de memória foram progressivamente piores nos grupos assintomático e HAM/TSP em comparação aos controles. Latência do P300 acima de 395ms e escore de autopercepção de memória abaixo de 7 pontos apresentaram sensibilidade e especificidade adequadas para detecção de comprometimento cognitivo tendo a avaliação neurológica como padrão ouro. A frequência de comprometimento cognitivo foi 40 vezes maior no grupo assintomático e 103 vezes maior no grupo HAM/TSP quando comparados aos controles. Observou-se elevada prevalência habilidades auditivas alteradas mesmo em indivíduos considerados assintomáticos (92%). Os testes dicótico de dígitos (p=0,031) e GIN (p=0,046) foram significativamente mais alterados no grupo HAM/TSP quando comparados ao grupo de assintomáticos. Os testes dicótico de dígitos, SSI, PPS, GIN e MLD conseguiram diferenciar participantes com e sem comprometimento cognitivo na amostra. Conclusão: O presente estudo ampliou a compreensão sobre a existência de um espectro amplo de manifestações clínicas e subclínicas na infecção pelo HTLV-1 ao agregar dados normativos de medidas subjetivas e objetivas do PAC e a autopercepção de memória entre indivíduos infectados em diferentes estágios da doença neurológica. O uso do escore de autopercepção de memória para queixas de memória do dia a dia na consulta médica foi um método útil e de fácil aplicação para a triagem de portadores assintomáticos do HTLV-1 quanto às alterações cognitivas.

Introduction: Infection with human T-cell lymphotropic virus type 1 (HTLV -1) has a wide spectrum of clinical manifestations, among which the HTLV-1-associated myelopathy / spastic tropical paraparesis (HAM/TSP) stands out. New diagnostic perspectives, such as the assessment of central auditory processing (CAP) can assist in the early identification of subclinical changes and cognitive impairment in the course of HTLV-1 infection. Objective: To evaluate the behavioral and electrophysiological responses of CAP in HTLV-1 infection and correlate them with self-perceived everyday memory. Methods: Cross-sectional comparative study nested in a cohort of former blood donors infected with HTLV-1 and uninfected controls matched for age, sex, and education. Self-perception of memory for everyday life was obtained by scoring from zero to 10 on a visual scale. The CAP was evaluated by auditory behavioral tests with dichotic listening tasks, low redundancy monaural speech, temporal ordering, temporal resolution, and binaural interaction, and by the cognitive evoked potential (P300). Results: The sample comprised 15 infected individuals with HAM/TSP, 20 asymptomatic infected, and 35 healthy seronegative controls. P300 latency and memory self-perception score were progressively worse in the asymptomatic and HAM/TSP groups compared to controls. P300 latency above 395ms and memory self-perception score below 7 points showed adequate sensitivity and specificity for detecting cognitive impairment having the neurological assessment as the gold standard for comparison. The frequency of cognitive impairment was 40 times higher in the asymptomatic group and 103 times higher in the HAM / TSP group when compared to controls. A high prevalence of altered auditory abilities was observed even in individuals considered asymptomatic (92%). The dichotic digit tests (p = 0.031) and GIN (p = 0.046) were significantly more altered in the HAM/TSP group when compared to the asymptomatic group. The dichotic digit tests, SSI, PPS, GIN, and MLD were able to differentiate participants with and without cognitive impairment in the sample. Conclusion: The present study expanded the understanding of the existence of a broad spectrum of clinical and subclinical manifestations in HTLV-1 infection by aggregating normative data of subjective and objective measures of the CAP and the self-perception of memory difficulties among infected individuals at different stages of the disease. neurological. The use of the memory self-perception score for complaints of everyday memory in the medical consultation was a useful and easy method for screening asymptomatic patients with HTLV-1 regarding cognitive changes.

Rinite crônica em portadores do HTLV-1: estudo histopatológico / Chronic rhinitis in HTLV-1 carriers: a histopathologic study

A histopatologia nasal de portadores do HTLV-1 com rinite crônica é desconhecida. OBJETIVO: Descrever aspectos histopatológicos de portadores do HTLV-1 com rinite crônica. CASUÍSTICA E MÉTODOS: Amostras de mucosa nasal de 10 portadores do HTLV-1 com rinite crônica, sendo oito com rinite alérgica e dois com rinite não alérgica, foram estudadas por microscopia de luz. Amostras de 10 pacientes com rinite alérgica não infectados pelo HTLV-1 serviram como controle. RESULTADOS: Fibrose subepitelial foi maior nos pacientes com rinite alérgica infectados pelo HTLV-1 (p=0,01), enquanto o espessamento da membrana basal foi maior nos controles (p=0,03). Houve tendência a menor eosinofilia e edema entre os infectados pelo HTLV-1, sem significância estatística (p=0,2). Para o infiltrado linfocítico, não houve diferença entre os pacientes com rinite alérgica infectados e não infectados (p=1,0). Fibrose subepitelial com infiltrado linfocítico de intensidade leve a moderada foram os achados encontrados nos dois portadores do HTLV-1 com rinite não alérgica. CONCLUSÕES: O estudo sugere que a infecção pelo HTLV-1 pode modificar a histopatologia da rinite alérgica, sobretudo por maior fibrose, e pode estar relacionada a uma rinite crônica não alérgica com infiltrado linfocítico.

The nasal histopathology of HTLV-1 carriers with chronic rhinitis is unknown. OBJECTIVE: To describe the histopathological features of HTLV-1 carriers with chronic rhinitis. MATERIALS AND METHODS: Biopsies of nasal mucosa of ten HTLV-1 carriers with chronic rhinitis (eight patients with allergic rhinitis and two patients with non-allergic rhinitis) were studied using a light microscope. Samples from ten patients with allergic rhinitis not infected with HTLV-1 were used as controls. RESULTS: Subepithelial fibrosis was more pronounced in patients with allergic rhinitis infected with HTLV-1 (p=0.01), while the basement membrane thickness was greater in controls (p=0.03). There was a trend towards less eosinophilia and edema among those infected with HTLV-1, without statistical significance (p=0.2). For the lymphocytic infiltrate, there was no difference between infected and not infected patients with allergic rhinitis (p=1.0). Subepithelial fibrosis associated to moderate or small number of lymphocytes were found in the two HTLV-1 carriers with non-allergic rhinitis. CONCLUSIONS: This study suggests HTLV-1 may modify the histopathology of allergic rhinitis, especially by promoting subepithelial fibrosis, and may be related to chronic non-allergic rhinitis with lymphocytic infiltrate.

Frequent HTLV-1 infection in the offspring of Peruvian women with HTLV-1-associated myelopathy/tropical spastic paraparesis or strongyloidiasis / Infección frecuente por HTLV-1 en los hijos de mujeres peruanas con mielopatía/paraparesia espástica tropical asociada con el HTLV-1 o con estrongiloidiasis

OBJECTIVES: To describe the frequency of HTLV-1 infection among offspring of mothers who had presented with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), strongyloidiasis, or asymptomatic HTLV-1 infection, and to identify factors associated with HTLV-1 infection. METHODS: In a descriptive study, records were reviewed of HTLV-1-positive women and their offspring who had been tested for HTLV infection at a public hospital in Lima, Peru, from 1989 to 2003. Sons and daughters of women who had presented with strongyloidiasis, HAM/TSP, or asymptomatic infection were eligible for this study. RESULTS: Three hundred seventy subjects were included: 279 were the offspring of 104 mothers presenting with HAM/TSP, 58 were the offspring of 22 mothers with strongyloidiasis, and 33 were the offspring of 26 asymptomatic mothers. Mean age of the offspring at the time of testing was 26 years (standard deviation 12). Nineteen percent of the offspring tested positive for HTLV-1: 6 percent (2/33) of those with asymptomatic mothers, 19 percent (52/279) among the offspring of mothers with HAM/TSP, and 31 percent (18/58) among the offspring of mothers presenting with strongyloidiasis On multiple logistic regression analysis, three factors were significantly associated with HTLV-1: (a) duration of breast-feeding (odds ratio [OR] = 15.1; [4.2-54.1] for 12 to 24 months versus less than 6 months breast-feeding); (b) clinical condition of the mother (OR = 8.3 [1.0-65.3] for HAM/TSP and OR = 11.5 [1.4-98.4] for strongyloidiasis in comparison with offspring of asymptomatic mothers); and (c) transfusion history (OR = 5.5 [2.0-15.2]). CONCLUSIONS: In addition to known risk factors for HTLV-1 transmission (duration of breast-feeding and history of blood transfusion), maternal HAM/TSP and strongyloidiasis were associated with seropositivity among offspring of HTLV-1-infected mothers.

OBJETIVOS: Describir la frecuencia de la infección por HTLV-1 en los hijos e hijas de madres diagnosticadas con mielopatía/paraparesia espástica tropical asociada con el HTLV-1 (M/PET-HTLV-1), estrongiloidiasis o infección asintomática por HTLV-1, e identificar los factores asociados con la infección por HTLV-1. MÉTODOS: Para este estudio descriptivo se revisaron los registros de mujeres positivas a HTLV-1 y de sus hijos evaluados con pruebas para la infección por HTLV en un hospital público de Lima, Perú, entre 1989 y 2003. Eran elegibles para este estudio los hijos y las hijas de las mujeres que se presentaron con estrongiloidiasis, M/PET-HTLV-1 o infección asintomática. RESULTADOS: En el estudio participaron 370 personas: 279 hijos de 104 madres con M/PET-HTLV-1, 58 hijos de 22 madres con estrongiloidiasis y 33 hijos de 26 madres asintomáticas. La edad promedio de los participantes en el momento de su prueba para HTLV era de 26 años (desviación estándar: 12 años). De las personas estudiadas, 19 por ciento resultaron positivas a la infección por HTLV-1: 6 por ciento (2/33) de los hijos de madres asintomáticas, 19 por ciento (52/279) de los hijos de madres con M/PET-HTLV-1 y 31 por ciento (18/58) de los hijos de madres con estrongiloidiasis. Según el análisis de regresión logística múltiple, tres factores se asociaron significativamente con la infección por HTLV-1: a) duración de la lactancia materna por 12_24 meses (razón de posibilidades [odds ratio, OR] = 15,1; intervalo de confianza de 95 por ciento [IC95 por ciento]: 4,2 a 54,1, frente a la lactancia materna por menos de 6 meses); b) que la madre presentara M/PET-HTLV-1 o estrongiloidiasis (OR = 8,3; IC95 por ciento: 1,0 a 65,3 y OR = 11,5; IC95 por ciento: 1,4 a 98,4, respectivamente, en comparación con los hijos de madres asintomáticas); y c) los antecedentes de haber recibido una transfusión sanguínea (OR = 5,5; IC95 por ciento: 2,0 a 15,2). CONCLUSIONES: Además de los factores de riesgo de la transmisión de la infección por HTLV-1 conocidos (duración de la lactancia materna y antecedentes de transfusión sanguínea), el diagnóstico materno de M/PET-HTLV-1 y el de estrongiloidiasis se asociaron significativamente con la infección por HTLV-1 en los hijos de madres seropositivas