Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK.

BACKGROUND: The natural history of HTLV-1-associated myelopathy (HAM) has been mainly described in HTLV-1 endemic countries such as Japan, Brazil and Martinique. OBJECTIVES: The authors describe the natural history of the largest cohort of patients with HAM living in the UK from 1993 to 2007. METHODS: Prospective, longitudinal study comparing clinical and virological outcome between first and last clinical visit. Incidence and cause of death were documented and the mortality calculated. RESULTS: 48 patients were included: 79.2% were female, 79.2% were of Afro-Caribbean origin, and 83.3% acquired HTLV-1 through breastfeeding or unprotected heterosexual intercourse. The mean age of onset was 46 years. The median durations from onset of symptoms to diagnosis and to last follow-up were 2 and 11.6 years. The median time of follow-up was 3.8 years. The most common first recalled symptom was unilateral leg weakness. The median times from onset to unilateral, bilateral walking aid and frame or a wheelchair were 11, 11.2, 11.3 and 18 years. The overall average deterioration in timed walk in patients whose need for aid did not change was 2 s/10 m/year. Three patients progressed rapidly and were unable to walk within 2 years. Six patients were slow/non-progressors. The mortality was 2.4/100 person year follow-up. The median HTLV-1 viral load remained unchanged at 14%. CONCLUSIONS: HAM is a slowly progressing chronic disease. Timed walk deteriorates by 2 s/10 m/year, and patients remain ambulant for 10 years but become wheelchair-dependent a decade later. HTLV-1 viral load remains high and unchanged over time regardless of clinical progression.

Paraparesia espástica progresiva asociada a HTLV-I en Chile: estudio y seguimiento de 121 pacientes por diez años / Progresive spastic paraparesis associated to HTLV-I in Chile

Revision is made to 121 Chilean patients with progressive adult spastic paraparesis (PSPs) associated to HTLV-I. Epidemiologic, clinical, diagnosis and associated illnesses aspects are analyzed as well as the pathogenesis. The follow-up of patients during several years allowed defining the evolutional profile, establishing the causes of death and studying the virus' behavior. Pathogenesis hypothesis arose from the neuropathological search to define the mechanisms of damage supported on immunohystochemical studies. It was confirmed that the CNS illness is a degenerative process linked to a central axonopathy which expresses flaws in the axoplasmic transport, particularly affecting the corticospinal tracts, although there is a more extended myeloencephalic involvement. Furthermore, the virus is capable of producing a multisystemic illness that may simultaneously involve the nervous system; the hematological system; the exocrine glands; the hepatic, lung, muscular and bone parenchymas.

Se revisan las paraparesias espásticas progresivas del adulto (PEPAs) producidas por el HTLV-I, en 121 pacientes chilenos. Se analizan los aspectos epidemiológicos, clínicos, diagnósticos, las enfermedades asociadas, y la patogenia. El seguimiento de los pacientes durante varios años permitió definir el perfil evolutivo, establecer las causas de muerte y estudiar el comportamiento del virus. De los casos con anatomía patológica surgieron hipótesis, que han permitido definir mecanismos de daño, sustentados en estudios inmunohistoquímicos. Se pudo confirmar que la enfermedad del SNC es un proceso degenerativo, vinculado a una axonopatía central que expresa fallas del transporte axoplásmico, que afecta particularmente la vía corticoespinal, aunque existe un compromiso más extenso mielo-encefálico. Además, el virus es capaz de producir una enfermedad multisistémica, que puede comprometer simultáneamente el sistema nervioso, el sistema hematológico, las glándulas exocrinas, el parénquima hepático, pulmonar, muscular y óseo.

Establishing phenotypic features associated with morbidity in human T-cell lymphotropic virus type 1 infection.

The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HT). Although it is widely believed that virus infection and host immune response are involved in the pathogenic mechanisms, the role of the immune system in the development and/or maintenance of HT remains unknown. We performed an analysis of the peripheral blood leukocyte phenotype for two different subcohorts of HTLV-1-infected individuals to verify the existence of similar immunological alterations, possible laboratory markers for HT. The leukocyte population balance, the activation status of the T lymphocytes, and the cellular migratory potential of T lymphocytes, monocytes, and neutrophils were evaluated in the peripheral blood of HTLV-1-infected individuals classified as asymptomatic individuals, oligosymptomatic individuals, and individuals with HT. Data analysis demonstrated that a decreased percentage of B cells, resulting in an increased T cell/B cell ratio and an increase in the CD8+ HLA-DR+ T lymphocytes, exclusively in the HT group could be identified in both subcohorts, suggesting its possible use as a potential immunological marker for HT for use in the laboratory. Moreover, analysis of likelihood ratios showed that if an HTLV-1-infected individual demonstrated B-cell percentages lower than 7.0%, a T cell/B cell ratio higher than 11, or a percentage of CD8+ HLA-DR+ T lymphocytes higher than 70.0%, this individual would have, respectively, a 12-, 13-, or 22-times-greater chance of belonging to the HT group. Based on these data, we propose that the T cell/B cell ratios and percentages of circulating B cells and activated CD8+ T lymphocytes in HTLV-1-infected patients are important immunological indicators which could help clinicians monitor HTLV-1 infection and differentiate the HT group from the asymptomatic and oligosymptomatic groups.

Evolution in a chronic RNA virus infection: selection on HTLV-I tax protein differs between healthy carriers and patients with tropical spastic paraparesis.

HTLV-I causes T-cell leukemia and tropical spastic paraparesis (TSP) in a minority of infected people, whereas the majority remain healthy. The virus differs little in sequence between isolates but has been shown to have a quasispecies structure. Using the Nei and Gojobori algorithm, we have shown that the proportion of nonsynonymous to synonymous changes in HTLV-I proviral tax gene sequences from healthy seropositive subjects (Dn/Ds = 0.9 to 1.3) is significantly higher than those from TSP patients (Dn/Ds = 0.3 to 0.6). Here we show that the distinction between healthy seropositives and TSP patients can only be seen with proviral tax sequences, but not with cDNA, the amino-terminal or carboxy-terminal half of tax, or the rex gene. The Dn/Ds ratio of proviral tax sequences was used to analyze two TSP patients with atypical features and to investigate the influence of cytotoxic T cells (CTL) on the viral quasispecies.

HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings.

We studied the clinical features and laboratory findings in 213 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis as diagnosed in Kagoshima University Hospital. Some aspects of clinical features in HTLV-I-associated myelopathy/tropical spastic paraparesis were characterized by mode of HTLV-I transmission and age of onset. The patients with onset after 15 years old and no history of blood transfusion before the onset of the disease (151 patients, group I) showed a shorter interval between the time of disease onset and that of inability to walk. The patients with onset before 15 years old and without history of blood transfusion (21 patients, group II) had short stature and slow progression of the disease. The interval time and the progression of the disease in patients with history of blood transfusion before onset of disease (41 patients, group III) were in between those of the above two groups. Patients whose ages of onset were older than 61 years old showed a faster progression than those with younger onset regardless of the mode of HTLV-I transmission. HTLV-I-associated myelopathy/tropical spastic paraparesis patients often also showed other organ disorders such as leukoencephalopathy (69%), abnormal findings on chest X-ray (50%), Sjögren syndrome (25%) and arthropathy (17%). The patients with low anti-HTLV-I antibody titers in the cerebrospinal fluid (2X-8X by PA method) had an older age of onset on average, milder clinical symptoms and lesser increase of neopterin in the cerebrospinal fluid than those in the high titer subgroup whose titers were higher than 1024X in cerebrospinal fluid regardless of the mode of HTLV-I transmission. We speculate that the clinical course of HTLV-I-associated myelopathy/tropical spastic paraparesis mainly shows a slow progression which consists of an initial progressive phase (probably an inflammatory phase) and a latter chronic phase, although some patients showed acute/subacute onset and rapid progression.