Revisiting Keratoconjunctivitis sicca associated with Human T-Cell Lymphotropic Virus Type 1: prevalence, clinical aspects and proviral load

ABSTRACT Background: The prevalence of keratoconjunctivitis sicca (KCS) associated with Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) (HTLV-1/KCS) has been estimated at around 37%, but its clinical manifestations are poorly described. Purpose: To determine the prevalence and associated factors of HTLV-1/KCS in a large cohort of HTLV-1-infected individuals living in Salvador, Brazil. Methods: A cross-sectional study was conducted between June 2004 and September 2017 at the Integrative and Multidisciplinary Center for HTLV in Salvador, Bahia-Brazil. Data from 758 HTLV-1-infected patients was collected. A complete ophthalmologic examination was performed in both eyes. Lacrimal function was evaluated by breakup time, Rose Bengal and Schirmer I Tests. KCS diagnosis was considered in the presence of at least two out of three positive tests. HTLV-1 proviral load Crude and Adjusted Prevalence Rates (PR) with 95% Confidence Intervals (95% CI) were estimated using multivariate Poisson Regression with robust error variance. Results: The overall prevalence of KCS was 31.7%, with higher rates observed in HTLV-1-associated myelopathy/tropical spastic paraparesis patients (crude PR: 1.84; CI95%: 1.50-2.26) even after adjusting for age, sex, time of HTLV-1 diagnosis and schooling (adjusted PR: 1.63; CI95%: 1.31-2.02). Proviral load, low corrected visual acuity, burning and/or pain and itching were all significantly higher in patients with KCS. Conclusion: Burning and/or pain and itching and low corrected visual acuity were the most common alterations of HTLV-1/KCS. High Proviral load was found to be associated with the presence of KCS. It is strongly recommended that HTLV-1 patients undergo periodic ophthalmologic examination to promote the early diagnosis of KCS and prevent the consequences associated with dry eye disease.

Avaliação de células T regulatórias e pefil de ativação de linfócitos T na ceratoconjuntivite seca associada ao HTLV-1 / Regulatory T cells evaluation and T lymphocyte activation profile in keratoconjunctivitis sicca associated with HTLV-1

O HTLV-1 é o agente etiológico da leucemia /linfoma de células T do adulto (ATLL), da paraparesia espástica tropical/ mielopatia associada ao HTLV-1 (HAM/TSP) e da uveíte. Além destas, a ceratoconjutivite seca (CCS), doença multifatorial da lágrima e da superfície ocular, tem sido descrita com maior frequência em indivíduos infectados pelo HTLV-1. Assim como em outras doenças associadas, a CCS tem sido relacionada a uma elevada carga proviral. As células T regulatórias (Treg) são importantes na manutenção da homeostase do sistema imunológico e um comprometimento da imunorregulação exercido por elas pode contribuir para o ambiente inflamatório observado na CCS. Este estudo objetivou avaliar os linfócitos Treg de pacientes com CCS associada à infecção pelo HTLV-1. Foram realizados ensaios de imunofenotipagem por citometria de fluxo para avaliar a frequência de linfócitos T ativados (HLA-DR+) e de células T CD4+ e CD8+ regulatórios (FOXP3+), bem como a produção de IL-10 e TGF-β por estas células. Foram avaliados 37 pacientes infectados pelo HTLV-1 e assintomáticos para HAM/TSP, sendo 27 com diagnóstico positivo para a manifestação ocular (CCS), 10 com diagnóstico negativo (ASS), além de 17 voluntários não infectados pelo vírus (NI). As frequências de linfócitos T CD4+FOXP3+, CD8+FOXP3+, CD4+HLA-DR+ e CD8+HLA-DR+ foram significativamente maiores nos grupos CCS e ASS, quando comparados aos indivíduos não infectados. Quanto à produção das citocinas imunossupressoras, foi observada uma maior frequência de linfócitos T CD4+FOXP3+ duplo produtores de IL-10 e TGF-β no grupo CCS quando comparado ao grupo ASS. Com relação aos linfócitos CD8+FOXP3+, o grupo CCS apresentou uma maior frequência de células mono produtoras de IL-10 quando comparado ao ASS. Nossos resultados sugerem que a menor frequência de células Treg CD8+ produtoras de TGF-β em indivíduos infectados pelo HTLV-1 com CCS, pode contribuir para a intensificação da ativação celular e fisiopatologia da doença.

HTLV-1 is the causative agent of leukemia/lymphoma adult T-cell (ATLL), tropical spastic paraparesis / myelopathy associated with HTLV-1 (HAM / TSP) and uveitis. In addition, keratoconjunctivitis sicca (KCS), a multifactorial disease of the tear and of the ocular surface, has been more frequently reported in patients infected with HTLV-1. As for other HTLV-1-associated diseases, KCS has been related to a high proviral load. Regulatory T (Treg) cells are important in maintaining the homeostasis of the immune system. An impairment in the immunoregulation function of Treg may contribute to the inflammatory environment observed in the KCS. This study aimed to evaluate the Treg cells of patients with KCS associated with HTLV-1. Frequency of activated T cells (HLA-DR+) and CD4+ and CD8+ Treg cells (FOXP3+), as well as IL-10 and TGF-β production by Treg were quantified using flow cytometry. Thirty-seven HTLV-1 individuals were included (27 asymptomatic for HAM/TSP with positive diagnosis of ocular manifestation (KCS), 10 with negative diagnosis (ASS - asymptomatic). Seventeen non-infected individuals were included as controls (NI). The frequencies of CD4+ FOXP3+ T cells, CD8+FOXP3+, CD4+HLA-DR+ and CD8+HLA-DR+ were significantly higher in KCS and ASS groups when compared to non-infected individuals. As the production of immunosuppressive cytokines, a higher frequency of CD4+ FOXP3+ double producers of IL-10 and TGF-β in the KCS group was observed when compared to group ASS. Regarding the CD8+FOXP3+ lymphocytes, the KCS group had a higher frequency of mono cells producing IL-10 when compared to the ASS. Our results suggest that the lower frequency of Treg cells CD8+ TGF-β-producing in individuals infected with HTLV-1 with KCS, may contribute to the intensification of cellular activation and pathophysiology of the disease.

Ocular lesions in HTLV-1 infected patients from Salvador, State of Bahia: the city with the highest prevalence of this infection in Brazil / Lesões oculares em pacientes infectados pelo HTLV-1 em Salvador, Estado da Bahia: a cidade com maior prevalência desta infecção no Brasil

In order to determine the prevalence of ocular lesions in HTLV-1 infected patients in Salvador Bahia, a transversal study was conducted on 140 HTLV-1 infected patients (90 asymptomatic and 50 tropical spastic paraparesis/HTLV-1-associated myelopathy) between June 2004 and November 2005. The ophthalmological examination included visual acuity measurement, ocular motility, biomicroscopy of the anterior and posterior chambers, intraocular pressure and evaluation of lachrymal secretion. Observation verified 4 (2.8 percent) out of 140 patients with uveitis (two patients had intermediate uveitis and two had pan-uveitis) and 39 (36.4 percent) out of 107 patients with keratoconjunctivitis sicca. The prevalence of Keratoconjunctivitis sicca was significantly higher among the TSP/HAM patients (OR age adjusted=3.64; 95 percentCI 1.59-8.32). Uveitis and corneal opacities were also important findings, indicating the strong need for periodic ophthalmological follow-up in all HTLV-1 subjects.

Com o objetivo de determinar a prevalência de lesões oculares, em portadores de HTLV-1 em Salvador, Bahia, foi realizado um estudo transversal em 140 pacientes (90 assintomático e 50 com paraparesia espática tropical/mielopatia associada ao vírus linfotrópico de células T humanas) entre junho de 2004 e novembro de 2005. O exame oftalmológico incluiu medida da acuidade visual, exame da motilidade ocular, biomicroscopia anterior e posterior, pressão intraocular e avaliação do filme lacrimal. Observamos 4.0 (2.8 por cento) pacientes com uveites (dois com uveíte intermediária e dois com panuveíte) e 39 (36,4 por cento) pacientes com ceratoconjuntivite seca. A prevalência de Ceratoconjuntivite seca foi significantemente mais elevada entre os pacientes com TSP/HAM (RC ajustada para idade = 3,64; IC 95 por cento 1,59-8,32). As uveítes e opacidades corneanas foram também, patologias importantes, indicando a necessidade de acompanhamento oftalmológico periódico nos portadores de HTLV-1.