A 43-year-old male applied for life insurance. He donated blood in 2001 and was found to be seropositive for Human T-cell Leukemia/Lymphoma Type 1 (HTLV-1) virus. He was last tested in 2008 and was ELISA and Western blot positive for HTLV-1. No proviral load was done. His parents were from Jamaica, but he was born in New York. He is being followed yearly with Complete Blood Counts which have been normal.
What is HTLV-1, and what are its mortality implications for testing positive?
HTLV-1 was the first human retrovirus discovered (1979). HTLV-1 predominantly affects T lymphocytes. HTLV retroviruses are RNA viruses that use an enzyme called reverse transcriptase to produce DNA from RNA.
|Figure 1 - HTLV-1 Virus|
HTLV-1 infection has been associated mainly with neurological, hematological and inflammatory diseases, especially HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATL/ATLL).
HTLV-1 is present worldwide with highly endemic areas in Japan, Melanesia, Australia, West Africa, the Caribbean, the United States (Central Florida), Central and South America and the region of Mashhad Iran (Figure 2). It is estimated that at least 10-25 million people worldwide are infected with HTLV-1.
|Figure 2 - Prevalence of HTLV-1 Worldwide|
In North America (outside of Florida), the prevalence of HTLV-1 seropositivity among blood donors is very low, on the order of 1 case per 10,000 blood donors.
HTLV-1 has three modes of transmission:
- Perinatal: 10%-25% of breastfed children born to mothers infected with HTLV-1 will be infected. The mother-child transmission is mainly associated with breastfeeding for over six months
- Sexual, occurring mainly from male to female
- Blood transfusion or transplantation of organs or tissues
HTLV-1 prevalence is strongly dependent on age and sex, with higher rates associated with older age and with female sex.
In the life cycle of HTLV-1, the viral RNA is transcripted (reverse transcription) into a DNA provirus that integrates into the host genome. New virions are produced via the viral integrated DNA.
HTLV-1 can infect different cell types; however, its spread is supported mainly by CD4+ cells. HTLV-1 infection induces the clonal proliferation of T-lymphocytes.
The majority of people infected by HTLV-1 remain asymptomatic. People who exhibit signs or symptoms usually are exposed to the infection for long periods before it becomes manifest.
Some factors contribute to the virus/host interaction and in progression from the asymptomatic state to the disease:
- Elevated proviral load is the most evident risk factor for transition from the asymptomatic carrier status to myelopathy and hematological disease
- Genetic host characteristics (Human Leukocytes Antigen) participate in the modulation of immune response and influence the development of symptomatic disease.
HTLV-I associated diseases are generally slow to progress, and the majority of persons infected remain asymptomatic for life:
- Adult T-cell leukemia/lymphoma is associated with the malignant proliferation of transformed leukocytes carrying HTLV-I provirus
- HLTV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction and mild sensory disturbance in the lower extremities directly related to HLTV-1 infection
- HTLV-1-infected individuals also are at increased risk of developing inflammatory diseases, such as alveolitis, Sjögren’s syndrome, uveitis, arthropathy and polymyositis.
Diagnosis & Treatment
The most common diagnostic test of HTLV-1 infection is antibody detection. The enzyme immunoassay (EIA) is commonly used, followed by a confirmatory Western Blot.
PCR assays have been developed to quantify viral presence (proviral DNA load). Some studies have established a link between high proviral load and disease evolution.
Asymptomatic seropositive patients should be followed with annual follow-up visits. Laboratory evaluation may be limited to a complete blood and WBC differential count.
Some prospective studies of HTLV-1 carriers identified increases in the absolute lymphocyte and platelet counts in active disease. Atypical lymphocytes (Flower Cells) may be observed in peripheral blood. In addition, hypergammaglobulinemia and false-positive syphilis test results can be seen.
Treatment of asymptomatic HTLV-1 carriers is not currently indicated. No treatment has demonstrated a real efficacy for symptomatic patients. Current clinical trials including monoclonal antibody therapy are ongoing for ATL/ATLL and HAM/TSP treatment.
The lifetime risk of developing adult T-cell leukemia/lymphoma (ATLL) has been estimated at 2%-6% among HTLV-1 carriers. The latency period is approximately 20 to 40 years after infection, with a slightly higher risk among HTLV-1 infected males. The risk of disease development increases among transfusion and transplant recipients, who may
develop the disease with a much shorter incubation time.
Among the associated malignancies, only smoldering ATL has a relatively good prognosis, with a five-year survival rate of 70%. For the other forms (chronic, acute or lymphoma) the prognosis at five years is poor.
The risk of developing HAM/TSP has been estimated at 0.25%–3.8% of infected persons. The prognosis of HAM/TSP is poor, with progression of neurologic deterioration and disability.
HTLV-1 infected persons are at risk of developing hematological or neurological diseases, but a majority of them are only carriers. However 2%-6% of them will develop a hematological malignancy with high mortality risk.
Returning to the Case
Approximately 95% of a cohort infected by HTLV 1 will not develop viral related diseases and can be expected to have population mortality. Approximately 5% are anticipated to have a reduced life expectancy due to viral related illness. Applying this ratio to varying reduced life expectancies in a 43-year-old male results in a mild to moderate extra mortality risk for the group as a whole.
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