HTLV infection and the eye.

PURPOSE OF REVIEW: Human T-cell lymphotropic virus (HTLV) is the first discovered retrovirus causing malignancy in human. HTLV infection affects host's ocular tolerance and causes various diseases in the eye. Here we discuss the manifestations, mechanisms, treatments, and future directions of HTLV-related ocular diseases. RECENT FININGS: Recent serological researches showed that the number of HTLV-1 carriers in metropolitan area was increasing, although seroprevalence of HTLV-1 in general population was decreased after screening serological tests in blood donors started. The most common clinical entity of uveitis was still HTLV-1 uveitis in HTLV-1 highly endemic area, but prevalence of HTLV-1 uveitis varies in different parts of the world. As for treatment of inflammation, tacrolimus and 5-azacytidine were reported to be effective for autoimmune manifestations in HTLV-1-related overlap syndrome (deratomyositis/Sjogren's syndrome) and HTLV-1-related myelodysplastic syndrome. Interleukin-2 receptor targeted therapies improved scleritis in patients with adult T-cell leukemia/lymphoma caused by HTLV-1. Basic researches identified that HTLV-1 tax and HTLV-1 basic leucine zipper factor play critical roles in the HTLV-1-related disease and are now being investigated as targeted therapies. SUMMARY: Development of modern molecular biology makes it possible to reveal deep insights of HTLV-1-related ocular diseases. Although effective therapies based on basic researches have been reported, further endeavor is necessary to establish much more specific treatments of the ocular diseases.

Study of autoantibodies in patients with keratoconjunctivitis sicca infected by the human T cell lymphotropic virus type 1.

Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in many regions of the world, including Brazil, and has been associated to several immunological manifestations such as arthritis, uveitis, dermatitis and Sjögren's syndrome. This study was intended to evaluate the frequency of autoantibodies in patients infected with HTLV-1 and manifesting keratoconjunctivitis sicca (KCS). HTLV-1 patients with KCS, enrolled in a reference ambulatory of the city of Salvador, were tested for autoantibodies such as antinuclear antibodies, rheumatoid factor, anti-SSA/Ro and anti-SSB/La. Two comparison groups were also included: (a) HTLV-1 patients without KCS and (b) seronegative patients with KCS. Correlation of proviral load (PVL) in HTLV-1 patients with presence or absence of KCS was also assessed. No autoantibodies were detected in HTLV-1 patients with KCS. The PVL of HTLV-1 patients was higher in patients with KCS without other clinical manifestations customarily associated to HTLV-1. In conclusion, in this study, no changes were observed in humoral immunity concerning production of certain autoantibodies in HTLV-1-infected patients with KCS, which suggests that other mechanisms may be involved in the pathogenesis of this manifestation. Additionally, PVL may be a marker of KCS development in these patients.

Conjunctival effects of canine distemper virus-induced keratoconjunctivitis sicca.

OBJECTIVE: This study compared the histopathology of canine distemper virus (CDV)-induced keratoconjunctivitis sicca (KCS) to non-infectious KCS in conjunctival tissues. ANIMALS STUDIED: Forty mongrel dogs were assigned to three distinct groups: (i) non-infectious KCS (G1, n = 10), (ii) CDV-induced KCS (G2, n = 20), and (iii) healthy animals without any ocular alterations (G3, n = 10). PROCEDURE: IgG titers and physical and ophthalmic examinations (e.g. Schirmer tear test [STT], tonometry, biomicroscopy, indirect biomicroscopy, and fluorescein test) were performed on all dogs. Conjunctival biopsies were collected and examined microscopically. RESULTS: Non-infectious and CDV-induced KCS demonstrated similar histopathological changes. Both types of KCS correlated with low STT, conjunctival hyperemia, mucopurulent ocular discharge, predominant lymphoplasmacytic infiltration, and acantholysis and keratinization of the ocular surface. G1 had lower conjunctival goblet cell counts than G3. Inclusion bodies were sporadically found in conjunctival samples of dogs from G2. The severity of ocular lesions in G1 and G2 did not correlate with the histopathological findings. CONCLUSIONS: Dogs with non-infectious and CDV-induced KCS had very similar conjunctival histopathology. Our findings suggest that the pathophysiology of CDV-induced KCS is likely to be the same as non-infectious KCS, that is, a result of lacrimal deficiency and inflammation of the ocular surface.

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

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.

[Ocular manifestations during hepatitis C infection]. / Objawy oczne u chorych zakazonych wirusem C zapalenia watroby (HCV).

Hepatitis C wirus is one of the major blood-born pathogens of huge epidemic value. Due to its easy transmission, lack of routinely pursued tests and long non-symptomatic period makes it crucial to be alert for all co-morbidites suggesting HCV infection. Consequently to reduce its farther transmission large knowledge of HCV should be spread as there is still no effective means of prophylaxis and its therapy is much costly. This article describes ophthalmic symptoms of hepatitis C virus infection such a mere keratoconiunctivitis sicca to ischemic retinopathy, macular edema and ischemic neuropathy.

Epstein-Barr virus dacryoadenitis resulting in keratoconjunctivitis sicca in a child.

PURPOSE: To describe a case of severe dry eye syndrome in a child. METHODS: Observational case report. The authors describe a 10-year-old male with severe dry eyes who was profoundly disabled by pain and photophobia despite aggressive conventional therapy. Lacrimal gland histology was consistent with the primary Sjögren syndrome, and serologic and immunohistologic evidence supported the hypothesis of Epstein-Barr virus causality. RESULTS: Treatment with systemic acyclovir and cyclosporin A resulted in dramatic and rapid reversal of the profound sicca syndrome and enabled the patient to resume his normal activities. CONCLUSION: Epstein-Barr virus dacryoadenitis should be considered in the differential diagnosis of keratoconjunctivitis sicca in children. Epstein-Barr virus can cause keratoconjunctivitis sicca, which can be treated successfully with acyclovir therapy in addition to suppression of the inflammatory response.

Investigating a viral etiology for keratoconjunctivitis sicca among patients who are positive for human immunodeficiency virus.

PURPOSE: Herpesvirus infection of the lacrimal gland was investigated as an etiologic factor for keratoconjunctivitis sicca in patients who were positive for human immunodeficiency virus (HIV). METHODS: In this cross-sectional study, we recorded the Schirmer tests and tear break-up times (TBUTs) among 30 patients who were positive for HIV. Dry-eye state was defined as a Schirmer test of <10 mm of wetting at 5 min or a TBUT of <10 s. The polymerase chain reaction assay (PCR) for herpes family viruses [Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV)] was performed on the conjunctival and tear specimens of the 30 HIV-positive patients by using virus-specific single primers. We compared the rates of virus DNA detection among dry-eye and non-dry-eye patients by calculating the odds ratio of detection for each virus. RESULTS: The odds ratio of viral DNA detection was adjusted for age, gender, race, CD4 count, and duration of HIV positivity. The adjusted odds ratios of EBV DNA detection among dry-eye to non-dry-eye patients were 1.30 (p = 0.79) and 0.97 (p = 0.98) by using Schirmer tests and TBUTs, respectively. For CMV, the adjusted odds ratios among dry-eye to non-dry-eye patients were 1.94 (p = 0.58) with Schirmer tests and 1.02 (p = 0.99) with TBUTs. HSV and VZV DNA were not detected in any samples. CONCLUSION: Our study does not support the role of herpesvirus infection of the lacrimal gland as a causative factor in the pathogenesis of dry eyes in patients positive for HIV.

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.

Keratoconjunctivitis sicca of human T cell lymphotropic virus type 1 (HTLV-1) infected individuals is associated with high levels of HTLV-1 proviral load.

BACKGROUND: A high HTLV-1 proviral load is found in HTLV-1-associated diseases, mainly HAM/TSP. However, the association between proviral load and keratoconjunctivitis sicca (KCS) has not been well established. AIM: To verify the association between KCS and HTLV-1 proviral load. STUDY DESIGN: 104 HTLV-1 infected patients (51 asymptomatic and 52 with HAM/TSP) from the HTLV reference center in Salvador, Brazil were followed from June 2008 to May 2010. Evaluation of tear secretion was performed by BUT (break-up time), Rose Bengal and Schirmer I tests. The diagnosis of KCS was based upon the presence of symptoms and when at least two of three tests were positive. HTLV-1 proviral load was determined using real-time PCR. RESULTS: The prevalence of KCS was 44.2%. KCS was more frequent among HAM/TSP patients (p = 0.022). Patients with KCS had higher proviral load (mean 134,672 ± 150,393copies/10(6) PBMC) than patients without the disease (mean 66,880 ± 109,525copies/10(6) PBMC) (p = 0.001). HTLV-1 proviral load>100,000copies/10(6) PBMC increased significantly the risk of developing KCS (OR = 4.05 and 95% CI = 1.40-11.76). After age>45 years and HAM/TSP status were excluded in stepway reward analysis, the variables PVL>100,000 (OR = 4.77 and 95% CI = 1.83-12.44) still remained statistically significant. CONCLUSION: HTLV-1 proviral loads are higher in patients with KCS and may represent a relevant biological marker of disease.

Ocular lesions in HTLV-1 infected patients from Salvador, State of Bahia: the city with the highest prevalence of this infection in Brazil.

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%) out of 140 patients with uveitis (two patients had intermediate uveitis and two had pan-uveitis) and 39 (36.4%) 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%CI 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.

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 manifestations of hepatitis C virus infection.

Approximately 3.6 million persons in the United States are infected with the hepatitis C virus (HCV), a condition with both hepatic and extrahepatic sequelae. Although no pathognomonic manifestation of HCV infection in the eye has been demonstrated, associations between HCV infection and various ocular syndromes have been reported in small case series and individual patients. At this time, the ocular manifestations of HCV infections best supported by the literature include a dry eye syndrome similar to Sjögren syndrome, and ischemic retinopathy caused by either an HCV-induced vasculitis or treatment with interferon. Patients with diabetes seem to be more susceptible to interferon retinopathy and to subsequent permanent visual loss. There have been no cases of HCV transmission via corneal transplantation, suggesting that current cadaveric screening protocols are effective in preventing this route of transmission. Screening for HCV should be considered in patients with risk factors for HCV infection who suffer from unexplained ischemic retinopathy or dry eyes.

Epstein-Barr virus (types 1 and 2) in the tear film in Sjogren's syndrome and HIV infection.

Evidence of Epstein-Barr virus (EBV) shedding in the saliva and tear film has been sought to explain the pathogenesis of the oral and ocular features of Sjogren's syndrome. Patients with human immunodeficiency virus (HIV) infection are purported to have a higher incidence of keratoconjunctivitis sicca. Twenty patients with definite Sjogren's syndrome (primary and secondary), 19 with HIV infection, and 15 normal controls were recruited and studied. Human herpes viruses (EBV 1 and 2, CMV, HZV, and HSV-1) in tear film were detected by polymerase chain reaction of DNA extracted from Schirmer strips. HSV-1, VZV, and CMV were not detected in any tear samples. EBV-1 DNA was found in the tear film of 4 patients with Sjogren's syndrome, which was not significantly different from the control group (P = 0.18). Twelve patients with HIV infection had evidence of EBV-1 in their tears, which was significantly different from controls (P = 0.0002) and patients with Sjogren's syndrome (P = 0.014). EBV-2 was found in 3 patients with HIV and in 1 patient with secondary Sjogren's syndrome, and was always found as a co-infection with EBV-1 (P = 0.01). This represents the first report examining EBV types 1 and 2 in the tear film and also EBV in the tear film of patients with HIV. Shedding of EBV in the tear film was not related to the presence of keratoconjunctivitis sicca in Sjogren's syndrome. EBV-2 co-infection with EBV-1 has not been previously reported in the tear film. EBV infection is abnormally regulated in Sjogren's syndrome and HIV, and it is likely that the presence of EBV in the tear film is related to the patients' altered immune status.

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.