Davi Tanajura

Immunopathogenesis and neurological manifestations associated to HTLV-1 infection

The human T lymphotropic virus type-1 (HTLV-1) was the first human retrovirus identified. The virus is transmitted through sexual intercourse, blood transfusion, sharing of contaminated needles or syringes and from mother to child, mainly through breastfeeding. In addition to the well-known association between HTLV-1 and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), several diseases and neurologic manifestations have been associated with the virus. This review was conducted through a PubMed search of the terms HTLV-1, immune response and neurological diseases. Emphasis was given to the most recent data regarding pathogenesis and clinical manifestations of HTLV-1 infection. The aim of the review is to analyze the immune response and the variety of neurological manifestations associated to HTLV-1 infection. A total of 102 articles were reviewed. The literature shows that a large percentage of HTLV-1 infected individuals have others neurological symptoms than HAM/TSP. Increased understanding of these numerous others clinical manifestations associated to the virus than adult T cell leukemia/lymphoma (ATLL) and HAM/TSP has challenged the view that HTLV-1 is a low morbidity infection.

Urinary tract infection in non-hospitalized patients with cirrhosis and no symptoms of urinary tract infection: a case series study

Bacterial infections are important factors in decompensation, and they increase the mortality rate of patients with liver cirrhosis. The most common infections among these patients are spontaneous bacterial peritonitis, pneumonia, skin infections and urinary tract infections (UTI). This transversal study evaluated the frequency of UTI in non-hospitalized patients with cirrhosis followed in a hepatology outpatient unit. Patients with clinical, laboratorial, echographic and/or histological diagnosis of cirrhosis were evaluated from April 2002 to August 2004. Patients who accepted participating in this study were submitted to clinical evaluation and the following laboratorial examinations: urine analysis, urine culture, blood culture and hepatic function tests. Patients with symptoms of UTI, diabetis, prostatic disease were excluded. Eighty-two patients with cirrhosis were studied. Their mean age was 51 years (SD = 11); 73% were male. Hepatitis C virus was the main etiology in 45% of the cases. The Child-Pugh B functional class was observed in 52% of the cases. Urine cultures were positive in 4.9% of these patients. In this study of non-hospitalized cirrhotic patients, with no symptoms of UTI, the frequency of urinary tract infection was approximately 5%. The bacteria found were E. coli and Klebsiella pneumonia. We conclude that it is necessary to screen for UTI in such patients.

Association between urinary symptoms and quality of life in HTLV-1 infected subjects without myelopathy

OBJECTIVE To investigate the relationship between urinary symptoms and quality of life of patients infected with HTLV-1. MATERIALS AND METHODS This is a cross-sectional study that enrolled individuals with HTLV-1 positive serology from February 2010 to March 2011. Participants were HTLV-1 infected subjects followed in the HTLV-1 clinic of the University Hospital in Salvador, Bahia, Brazil. Patients with HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP), who had evidence of other neurological diseases, diabetes mellitus or were pregnant were excluded from the study. The questionnaire SF-36 was used to evaluate quality of life and the questionnaire OAB-V8 was used to evaluate urinary symptoms. RESULTS From the 118 individuals evaluated, 50 (42.4%) complained of urinary symptoms and 68 (57.6%) did not. Most participants were females. There was no difference between the groups regarding demographic variables. The group with symptoms showed significantly lower scores in all domains of the SF-36 questionnaire. The domains with greatest differences were vitality and general health state. CONCLUSIONS Urinary symptoms negatively influence the quality of life of individuals infected with HTLV-1.

The clinical spectrum of HTLV-1 infection

The Human T lymphotropic virus type 1 (HTLV-1) infection is neglected mainly due to the concept that it is associated with a low morbidity. However, a few reports have shown that a large percentage of HTLV-1 infected subjects have signs and symptoms of a variety of diseases. Nevertheless the relationship between the cause and effect needs to be proven. The HTLV-1 associated myelopathy (HAM/TSP) and adult T-cell leukemia (ATL), the main disease associated to HTLV-1, are characterized by high proviral load and lymphocyte activation. Moreover the exaggerated inflammatory response and proviral load are markers of diseases associated with HTLV-1. In this study we compare the frequency of sicca syndrome, chronic periodontal disease (CPD), HTLV-1 associated over reactive bladder (HTLV-1 OAB), artropathy and erectile dysfunction (ED) in HTLV-1infected subjects who did not have definitive HAM/TSP with that observed in seronegative controls. The proviral load was measured by real time PCR and production of interferon–γ and TNF in supernatants of lymphocyte culture by ELISA. Of the 180 individuals participants of the study, 106 (50.8%) were female, 56 (31.1%) had sicca syndrome, 37 (20.5%) had CPD, 32 (17.7%) had HTLV-1 OAB, 29 (16.6%) had HTLV-1 associated arthropathy. Moreover of the 74 males 31 (41.8%) had ED. All these manifestations were higher (P<0.001) in HTLV-1 infected subjects than in controls. Proviral load in sicca syndrome, CPD, HTLV-1 OAB and ED patients were higher (P < 0.05) than in 78 (43,3%) HTLV-1 carriers. Patients with OAB, CPD and sicca syndrome had higher TNF and IFN-γ than HTLV1 carriers. The majority of the patients with diseases associated to HTLV1 had at least two of the above diseases. Overall 56,7% of HTLV-1 infected subjects without definitive HAM/TSP or ATL had diseases associated with HTLV1 infection indicating that HTLV-1 is associated with high morbidity.

Clinical manifestations in HTLV-1 infected individuals without HAM/TSP: Results of an 8 years cohort

HTLV-1 is an endemic virus in the northeast of Brazil and is related to HAM/TSP in up to 5% of infected individuals. Despite this low prevalence it is known that a higher number of carriers presents with clinical and neurological symptoms that can be sensory, motor, urinary, inflammatory or autonomic.

Local and systemic production of proinflammatory chemokines in the pathogenesis of HAM/TSP

BACKGROUND HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is related with high proviral load, high proinflammatory cytokine levels, and passage of infected cell from the blood to the central nervous system. We aimed to evaluate the participation of chemokines and adhesion molecules in HAM/TSP pathogenesis. METHODS CXCL9, CXCL10, sICAM-1, and sVCAM-1 were determined by ELISA in serum and cerebrospinal fluid (CSF) of HTLV-1 infected individuals. The frequency and median fluorescence intensity (MFI) of lymphocytes and monocytes expressing ligands of adhesion molecules (CD11a and CD49d) and a chemokine receptor (CXCR3) were analyzed by flow cytometry. RESULTS The levels of CXCL9 and CXCL10 in serum of definite HAM/TSP were higher than in serum of probable HAM/TSP and HTLV-1 carriers. Considering the production of chemokines by patients with definite HAM/TSP, CXCL9 levels were higher in serum than in CSF, and CXCL10 production was higher in CSF than in serum. Levels of adhesion molecules in serum and CSF of HTLV-1 infected individuals did not differ. The MFI of CD11a on CD4+, CD8+ and CD14+ cells was lower in definite HAM/TSP than in HTLV-1 carriers and did not differ from probable HAM/TSP and healthy subjects (HS). The frequency of lymphocytes expressing CXCR3 was lower in definite HAM/TSP than in cells of probable HAM/TSP and did not differ from carrier and HS. CONCLUSION These data point to the participation of proinflammatory chemokines, especially CXCL10, in the pathogenesis of definite HAM/TSP.

Onabotulinumtoxin type A improves lower urinary tract symptoms and quality of life in patients with human T cell lymphotropic virus type 1 associated overactive bladder

AIM To evaluate the efficacy of the onabotulinum toxin type A in the treatment of HTLV-1 associated overactive bladder and its impact on quality of life (QoL). METHODS Case series with 10 patients with overactive bladder refractory to conservative treatment with anticholinergic or physical therapy. They received 200Ui of onabotulinumtoxin type A intravesically and were evaluated by overactive bladder symptoms score (OABSS) and Kings Health Questionnaire. RESULTS The mean (SD) of the age was 52+14.5 years and 60% were female. All of them had confirmed detrusor overactivity on urodynamic study. Seven patients had HAM/TSP. The median and range of the OABSS was 13 (12-15) before therapy and decreased to 1.0 (0-12) on day 30 and to 03 (0-14) on day 90 (p<0.0001). There was a significant improvement in 8 of the 9 domains of the Kings Health Questionnaire after the intervention. Hematuria, urinary retention and urinary infection were the complications observed in 3 out of 10 patients. The mean time to request retreatment was 465 days. CONCLUSION Onabotulinum toxin type A intravesically reduced the OABSS with last long effect and improved the quality of life of HTLV-1 infected patients with severe overactive bladder.

Detrusor Arreflexia as an End Stage of Neurogenic Bladder in HAM/TSP?

The HTLV-1 virus is a known agent involved in the development of HAM/TSP. Past studies have typically observed patients with autonomic dysfunction consisting of detrusor overactivity and detrusor-sphincter dyssynergia, with the occasional observation of underactive detrusor or detrusor arreflexia. However, studies have not yet evaluated the progression of neurogenic bladder over time. In this paper, we describe a HAM/TSP patient with the initial development of overactive detrusor, and subsequent development of detrusor arreflexia. Given a paucity of studies characterizing the effects of HTLV-1 on the autonomic nervous system, particularly aspects controlling continence, this patients clinical course may represent one type of end point for patients with HAM/TSP and neurogenic bladder. Further cohort or case-series studies, with particular emphasis on the progression of neurogenic bladder, are needed to evaluate the significance of this described case in relation to typical disease progression patterns.