Jerusa Smid

Corticosteroid therapy in TSP/HAM patients: the results from a 10 years open cohort.

BACKGROUNDnThe use of corticosteroids for treating tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) has yielded controversial results. We report the use of corticosteroids for the treatment of TSP/HAM in an open cohort.nnnMETHODSnThe clinical efficacy of long-term, high dose of corticosteroid therapy was studied in thirty-nine TSP/HAM patients. Disability and motor dysfunction was evaluated based on the Disability Status Scale (DSS), Osames Motor Disability Scales (OMDS), and Incapacity Status Scale (ISS), before and after treatment. Treatment included use of methyl-prednisolone, 1 g/day for three days, every 3-4 months. The primary end-point was a change in the scores of the neurological scales from baseline until the fifth visit after therapy.nnnRESULTSnAfter a mean follow-up of 2.2 years and an average of four pulses per patient, we noted a significant neurological improvement, reaching 24.5% according to the ISS score. No statistically significant differences in scores according to the OMDS and DSS scales were noted.nnnCONCLUSIONnWe observed neurological improvement with the use of corticosteroids, with physical therapy and antispastic-drugs as adjunctive treatment. However, randomized clinical trials should be done to assess the use of corticosteroids and other potentially useful immune-based therapies for TSP/HAM treatment.

The elevated interferon gamma production is an important immunological marker in HAM/TSP pathogenesis.

Human T‐lymphotropic virus type 1 (HTLV‐1) is the agent of the HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may occur in >5% of patients during their lifetime. HTLV‐1‐infection causes disturbances in the immune system, and the viral load may also play an important role in the pathogenesis of HAM/TSP. Some cytokines are involved in the pathogenesis of this disorder. We have determined IL‐2, IL‐4, IL‐10, IL‐12 p70, IFN‐γ and TNF‐α production among HTLV‐1‐infected subjects from our HTLV‐out Clinic in Institute of Infectious ‘Emílio Ribas’ in Sao Paulo city, Brazil. PBMC obtained from healthy controls (nu2003=u200332), asymptomatic HTLV‐1 carriers (nu2003=u200368) and HAM/TSP patients (nu2003=u200344) were grown in the absence and in the presence of phytohaemagglutinin (PHA), and the supernatants’ fluids were measured for cytokines production. IL‐2 levels were increased in the asymptomatic HTLV‐1 carriers, and IFN‐γ was increased in both groups of patients (asymptomatic HTLV‐1 carriers and more significantly among HAM/TSP patients). IL‐4, IL‐10, TNF‐α and IL‐12 p70 levels were not significantly increased on both groups of patients, as compared with controls. The major finding of this study is that IFN‐γ was an important cytokine for the HAM/TSP pathogenesis. Therefore, immune modulation of IFN‐γ may be critical to treat of HAM/TSP patients.

Presence of tropical spastic paraparesis/human T‐cell lymphotropic virus type 1‐associated myelopathy (TSP/HAM)‐like among HIV‐1‐infected patients

Human immunodeficiency virus type 1 (HIV‐1) and human T‐cell lymphotropic virus types 1 and 2 (HTLV‐1 and ‐2) are retroviruses that share similar routes of transmission and some individuals may have a dual infection. These co‐infected subjects may be at increased risk for tropical spastic paraparesis/HTLV‐1‐associated myelopathy (TSP/HAM)‐like. To study the prevalence of tropical spastic paraparesis/HTLV‐1‐associated myelopathy (TSP/HAM) among co‐infected HIV‐1/HTLV‐1 subjects. Since July 1997, our group has been following a cohort to study the interaction of HTLV with HIV and/or hepatitis C virus (HCV), as well as HTLV‐1‐only infected asymptomatic carriers or those already presenting with TSP/HAM. During these 9 years, 296 HTLV‐1‐infected individuals were identified from a total of 538 patients who were referred to our clinic at the Institute of Infectious Diseases “Emílio Ribas,” in São Paulo, Brazil. All subjects were evaluated by two neurologists, blinded to the HTLV status. TSP/HAM diagnosis was based on Kagoshima diagnostic criteria. Results: A total of 38 HIV‐1/HTLV‐1 co‐infected subjects were identified in this cohort: Twenty‐six had already been diagnosed with AIDS and 12 remained asymptomatic. Six of 38 co‐infected subjects (18%) were diagnosed as having TSP/HAM and also AIDS, and for 5 of them TSP/HAM was their first illness. One additional incident case was diagnosed after 2 years of follow‐up. No modifications on HIV‐1 viral load was seen. In contrast, the co‐infected with TSP/HAM‐like group showed higher HTLV‐1 proviral load (505u2009±u2009380 vs. 97u2009±u2009149 copies/104 PBMC, Pu2009= 0.012) than asymptomatic co‐infected subjects, respectively. The incidence of myelopathy among HIV‐1/HTLV‐1 co‐infected subjects is probably higher than among patients infected only with HTLV‐1, and related to a higher HTLV‐1 proviral load. Thus, HTLV‐1/2 screening should be done for all HIV‐1‐infected patients in areas where HTLV‐1 infection is endemic. J. Med. Virol. 80:392–398, 2008.

Detection of human T-cell lymphotropic virus type 1 in plasma samples.

Human T-cell lymphotropic virus type 1 (HTLV-1) is an RNA virus responsible for diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATL). Cell-to-cell contact and Tax-induced clonal expansion of infected cells are the main modes of virus replication, making virus detection during the viremic stage difficult. Consequently, the proviral load is the current virologic marker for disease monitoring, but the mechanisms of progression have not been established yet. Thus, this study investigated the presence of virus in plasma from asymptomatic HTLV-1 carriers and from HAM/TSP patients. Real-time PCR was performed on DNA from 150 plasma samples; 12 (8%) had detectable DNA amplification, including 6 (4%) asymptomatic HTLV-1 carriers and 14 (26%) HAM/TSP patients (p<0.005). Of the 33 samples submitted for nested PCR, six (18%, p=0.02) were positive for HTLV-1 RNA in the plasma. Additionally, 26 plasma samples were treated with DNAse enzyme to eliminate any DNA contamination before RNA extraction. Two of them (8%) showed amplification for HTLV-1 (p=0.5). Therefore, this study described for the first time the detection of free HTLV-1 RNA in plasma from HTLV-1-infected subjects, regardless of their clinical status. Thus, HTLV-1 viral replication does occur in plasma, and other transmission pathways for HTLV-1 should be investigated further.

T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)

INTRODUCTIONnHIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event.nnnOBJECTIVEnTo study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells.nnnMATERIAL AND METHODSnSince 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases Emílio Ribas, São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patients HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event.nnnRESULTSnA total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm(3) and 89 (53-196) cells/mm(3) for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30%) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event.nnnDISCUSSIONnOur results indicate that higher T CD4+ cells count among HIV-1/HTLV-1-coinfected subjects was found in 12% of the patients who presented an AIDS-defining event. These subjects also showed a TSP/HAM simile picture when it was the first manifestation of disease; this incidence is 20 times higher than that for HTLV-1-only infected subjects in endemic areas.

High production of RANTES and MIP-1α in the tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)

Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with progressive neurological disorders and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). The pathogenesis of TSP/HAM is considered as immune mediated, involving cytotoxic T cell (CTL) responses to a number of viral proteins and notably the regulation protein Tax. T CD8+ cells produce beta-chemokines, which are important in the anti-viral response. In the present study, we have analyzed the CC chemokines (RANTES, MIP-1beta and MIP-1alpha) production in retrovirus-infected subjects. A total of 191 subjects were studied: 52 healthy controls, 72 asymptomatic HTLV-1-infected carriers and 67 TSP/HAM patients. Peripheral blood mononuclear cells were maintained in the presence or absence of PHA, and supernatant fluids were assayed using EIA. MIP-1beta concentration was not significantly different across groups, but RANTES and MIP-1alpha concentrations showed significant differences when the three groups were compared. In TSP/HAM patients, the increase in the production of chemokines may lead to a recruitment of pro-inflammatory factors, contributing to the membranes myelin damage.

Prevalence of anxiety, depression and quality of life in HTLV-1 infected patients

UNLABELLEDnThe HAM/TSP caused by HTLV-1 infection usually affects patients to disabling states, and sometimes can lead them to paraplegia presenting symptoms of depression and anxiety, impacting on quality of life.nnnOBJECTIVEnThe purpose of this study was to evaluate the frequency of depression and anxiety and its impact on quality of life in HTLV-1-infected TSP/HAM patients.nnnMATERIAL AND METHODSnThis was a cross-sectional study including 67 asymptomatic (control group) and 63 with TSP/HAM subjects. The instruments used were a demographic questionnaire, scales for anxiety and depression diagnosis (BDI and BAI), questionnaire for the assessment of Quality of Life of the World Health Organization (WHOQOL-Brief) and neurological scale to measure the disability level (Osames Disability Status Scale). All patients had HTLV-I diagnosis by serological and molecular approaches, monitored at Instituto de Infectologia Emílio Ribas from May 2008 to July 2009. Data were analyzed statistically by frequencies, the Mann-Whitney test and the Spearman correlation test. Data among groups were analyzed and correlated with functional and severity aspects.nnnRESULTSnThe results showed that patients with HAM/TSP compared to asymptomatic carriers had higher rates of depression (p < 0.001) and anxiety (p < 0.001), and impairment on quality of life in the areas of: dissatisfaction with health (p < 0.001), physical (p < 0.001) and the environment (p = 0.003). The main factors that correlated with levels of depression and anxiety and the domains of the WHOQOL-brief were: education, family income and social class.nnnCONCLUSIONnA well conducted evaluation and counseling may help in treatment, for a better quality of life of these patients.

Low DNA HTLV-2 proviral load among women in Sao Paulo City

BACKGROUNDnHTLV-2 infections are almost always asymptomatic, and diseases associated with the infection are rarely reported. Little information is available on the relationship between HTLV-2 proviral load and gender or expression of disease, especially among patients with HIV-1 co-infection.nnnMETHODSnWe studied 77 HTLV-2-infected subjects followed in our clinic for the last 9 years; 53 (69%) of them were co-infected with HIV-1. HTLV-2 DNA proviral load (PVL) was measured by real time PCR, a test with a sensitivity of 10 in 10(4) PBMCs.nnnRESULTSnSix of 53HTLV-2/HIV-1 cases had a myelopathy (all of them had undetectable PVL of HTLV-2). Only 3 of 35 women (2 out of 3 co-infected with HIV) had a detectable PVL, whereas 10 of 42 men had a detectable PVL. Regardless of their HIV status women had significantly lower PVL than men (10 vs. 43 copies/10(4) PBMCs, p<0.05).nnnCONCLUSIONSnWe noticed the occurrence of myelopathy in HTLV-2/HIV-1 co-infected patients, with undetectable HTLV-2 viral load. There was a sex difference in viral load for HTLV-2, what may be the result in mode of transmission or acquisition of the virus.

High Prevalence of Skin Disorders among HTLV-1 Infected Individuals Independent of Clinical Status

Background Human T-cell lymphotropic virus type 1 (HTLV-1) infection can increase the risk of developing skin disorders. This study evaluated the correlation between HTLV-1 proviral load and CD4+ and CD8+ T cells count among HTLV-1 infected individuals, with or without skin disorders (SD) associated with HTLV-1 infection [SD-HTLV-1: xerosis/ichthyosis, seborrheic dermatitis or infective dermatitis associated to HTLV-1 (IDH)]. Methods A total of 193 HTLV-1-infected subjects underwent an interview, dermatological examination, initial HTLV-1 proviral load assay, CD4+ and CD8+ T cells count, and lymphproliferation assay (LPA). Results A total of 147 patients had an abnormal skin condition; 116 (79%) of them also had SD-HTLV-1 and 21% had other dermatological diagnoses. The most prevalent SD-HTLV-1 was xerosis/acquired ichthyosis (48%), followed by seborrheic dermatitis (28%). Patients with SD-HTLV-1 were older (51 vs. 47 years), had a higher prevalence of myelopathy/tropical spastic paraparesis (HAM/TSP) (75%), and had an increased first HTLV-1 proviral load and basal LPA compared with patients without SD-HTLV-1. When excluding HAM/TSP patients, the first HTLV-1 proviral load of SD-HTLV-1 individuals remains higher than no SD-HTLV-1 patients. Conclusions There was a high prevalence of skin disorders (76%) among HTLV-1-infected individuals, regardless of clinical status, and 60% of these diseases are considered skin disease associated with HTLV-1 infection.

Neither molecular diversity of the envelope, immunosuppression status, nor proviral load causes indeterminate HTLV western blot profiles in samples from human T-cell lymphotropic virus type 2 (HTLV-2)-infected individuals.

Although human T‐cell lymphotropic virus type 2 (HTLV‐2) is considered of low pathogenicity, serological diagnosis is important for counseling and monitoring. The confirmatory tests most used are Western blot (WB) and PCR. However, in high‐risk populations, about 50% of the indeterminate WB were HTLV‐2 positives by PCR. The insensitivity of the WB might be due to the use of recombinant proteins of strains that do not circulate in our country. Another possibility may be a high level of immunosuppression, which could lead to low production of virus, resulting in low stimulation of antibody. We found one mutation, proline to serine in the envelope region in the position 184, presented at least 1/3 of the samples, independent the indeterminate WB profile. In conclusion, we found no correlation of immune state, HTLV‐2 proviral load, or env diversity in the K55 region and WB indeterminate results. We believe that the only WB kit available in the market is probably more accurate to detect HTLV‐1 antibodies, and some improvement for HTLV‐2 detection should be done in the future, especially among high‐risk population. J. Med. Virol. 82: 837–842, 2010.