Human T-cell lymphotropic virus type I (HTLV-I) is etiologically associated with adult T-cell leukemia/lymphoma (ATLL); tropical spastic paraparesis (TSP), a demyelinating neurological disorder; and HTLV-I-associated myelopathy (HAM). Two types of HTLV testing are available - antibody and molecular testing.
Quick Answers for Clinicians
Diagnosis
Indications for Testing
- Adult T-cell leukemia/lymphoma (ATLL)
- Fatigue, rash, lymphadenopathy, accompanied by lymphocytosis, hypercalcemia, and elevated lactate dehydrogenase (LDH)
- Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paresis (HAM/TSP)
- Muscle pain, stiffness, and weakness (myalgias and myopathy)
- Changes in bowel and/or bladder function
- Other neurological signs and symptoms including peripheral paresthesias and dysesthesias, hyperreflexia, tremor, deafness, changes in vision
- Muscle pain, stiffness, and weakness (myalgias and myopathy)
Criteria for Diagnosis
ATLL subtypes and diagnostic criteria (Gonçalves, 2010)
Laboratory Testing
- Required evaluation for ATLL (Shimoyama, 1991)
- Peripheral blood smear – ATLL cells present
- HTLV-I testing
- HTLV-I and -II antibodies by enzyme immunoassay (EIA)/Western blot
- Initial testing
- HTLV-II antibodies significantly cross-react to HTLV-I antigens
- Populations such as parenteral drug abusers infected with HTLV-II may test positive for HTLV-I antibodies due to antibody cross-reactivity
- No evidence to suggest HTLV-II causes human disease
- Asymptomatic patients with HTLV-I antibodies
- May be infected and should not donate blood
- Often do not have ATLL or TSP and may not develop ATLL, HAM, or TSP
- Repeat Western blot testing for indeterminate results – 2 weeks and/or 3 months after initial testing
- HTLV-I, II polymerase chain reaction (PCR) – use to resolve untypable HTLV Western blot results when there is a strong suspicion of HTLV infection
- HTLV-I and -II antibodies by enzyme immunoassay (EIA)/Western blot
- Cerebrospinal fluid (CSF) studies
- Protein – increased
- Cell differential – lymphocytic pleocytosis
- HTLV antibodies – positive
- Oligoclonal bands – positive
- IgG index – high
- Bone marrow exam – generally not required
Histology
- If diagnosis not obtained by above, perform lesion biopsy (if present)
- Immunophenotyping
- Minimum testing should include CD3, CD4, CD7, CD8, and CD25
- Most ATLL cells lack CD7, CD52 with diminished CD3
- CD4+ T-cells express CD2, CD5, CD25, CD45RO, CD29
- CD7 and CD26 negative and CD3 expression diminished
Imaging Studies
- Computed tomography (CT) – recommend neck, thorax, abdomen, and pelvis to exclude extranodal disease
- Upper gastrointestinal endoscopy
- Central nervous system evaluation by CT/magnetic resonance imaging (MRI) if neurologic signs evident
Prognosis
- Poor prognosis risk factors
- Serum LDH elevated
- Serum calcium elevated
- Age ≥40
- Three or more lesions
- Additional – thrombocytopenia, eosinophilia, high IL5, p53 or p16 deletion
Differential Diagnosis
- HAM/TSP
- Infectious
- HIV
- Polio virus
- Mycobacterium tuberculosis
- Epidural abscess
- Tropical pyomyositis
- Treponema pallidum
- Fungal (eg, Cryptococcus sp, Histoplasma capsulatum)
- Multiple sclerosis
- Neurodegenerative
- Amyotrophic lateral sclerosis
- Friedreich ataxia
- Myopathic
- Inflammatory myopathies
- Genetic myopathies
- Paraneoplastic syndromes
- Inflammatory diseases
- Sarcoidosis
- Sjögren syndrome
- Systemic lupus erythematosus
- Malignant
- Bony or epidural metastases
- Primary intra/extra dural tumor
- Nutritional
- B12 deficiency
- Copper overload
- Infectious
- ATLL
- Peripheral T-cell lymphoma (not otherwise specified [NOS])
- Anaplastic large cell lymphoma (ALCL)
- Mycosis fungoides/Sézary syndrome
- Angioimmunoblastic T-cell lymphoma
Background
Epidemiology
- Prevalence
- 15-20 million infected with HTLV-I worldwide
- Endemic in Japan, Caribbean countries, Papua New Guinea, and sub-Saharan Africa
- Age
- ATLL – mean 60 years
- HAM/TSP – 40s-50s
- Sex
- ATLL – M>F
- HAM/TSP – M<F
- Transmission
- Parenteral
- Sexual
- Breastfeeding
- Lifetime risk of disease in presence of HTLV-I antibodies is low
- ATLL – men have increased risk for progression compared to women
- HAM/TSP – 0.5-4%
Organism
- HTLV-I and HTLV-II are human type C retroviruses
- Several subtypes exist that are geographically specific
- HTLV-I – six subtypes (A-F)
- Single-stranded RNA virus
- Several subtypes exist that are geographically specific
- Majority of human infections caused by HTLV-I
- HTLV and AIDS
- HTLV-I does not cause AIDS
- Antibodies of HTLV-I have no relationship to antibodies of HIV type I (HIV-I)
- Antibodies to HTLV-I do not imply excess risk for AIDS
- HTLV-I virus is only remotely related to HIV-I, the AIDS virus
- HTLV-I and HTLV-II are transmitted similarly to HIV-I and HIV-II
- Individuals with HTLV-I or HTLV-II may be coinfected with HIV due to common risk factors (eg, sexual contact, IV drug use)
Risk Factors
- Cellular blood products – most efficient mode of transmission
- Breast milk – 20% of children of infected mothers will also become infected
- Sexual contact – associated with unprotected sex, multiple partners, presence of genital sores, sex exchanged for drugs or money
- Sharing of contaminated needles and syringes (eg, IV drug use)
- HTLV-I positive mother – perinatal transmission may occur
- Poverty
Clinical Presentation
- ATLL
- 4 types – acute, chronic, smoldering, lymphoma
- Acute ATLL most common
- Rapidly fatal without treatment
- Pulmonary complications, opportunistic infections, sepsis
- Uncontrolled hypercalcemia may occur
- TSP and HAM
- Slowly progressive spastic paraparesis – disease is usually present 8-10 years before diagnosis
- Prominent weakness of lower extremities with severe spasticity
- Upper extremity weakness rare
- Mild sensory impairment
- Hyperreflexia is often present
- Neuropathic pain is common in advanced stage
- Bladder/bowel/sexual dysfunction later in disease – urinary tract infections, lithiasis, chronic pyelonephritis, chronic renal failure
- Other associated diseases
- Ichthyosis
- Uveitis/keratoconjunctivitis
- Sjögren syndrome, rheumatoid arthritis
- Chronic alveolitis
- Inclusion body myositis/polymyositis
ARUP Laboratory Tests
Screen for antibodies to HTLV-I and -II
Assay should not be used for blood donor screening, associated reentry protocols, or for screening human cell, tissues, and cellular and tissue-based products
Qualitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot
Resolve untypable HTLV Western blot results when there is a strong suspicion of HTLV infection
Real-Time Polymerase Chain Reaction
Confirm antibody test results for a positive screening test (HTLV-I/II)
Assay should not be used for blood donor screening, associated reentry protocols, or for screening human cell, tissues, and cellular and tissue-based products
Qualitative Western Blot
Aid in evaluation of hematopoietic neoplasms (ie, leukemia, lymphoma)
Specimens include bone marrow, whole blood, tissue, or fluid
Monitor therapy in patients with established diagnosis of hematopoietic neoplasms
Markers selected based on provided clinical history and/or previous test results
Flow Cytometry
Antigens included:
T cell: CD1a, CD2, CD3, CD4, CD5, CD7, CD8, TCR γ-δ, cytoplasmic CD3
B cell: CD10, CD19, CD20, CD22, CD23, CD103, CD200, kappa, lambda, cytoplasmic kappa, cytoplasmic lambda
Myeloid/monocyte: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase
Miscellaneous: CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2, CD123, CD138, CD26, CD45, CRLF-2
Quantitative Enzymatic
Quantitative Spectrophotometry
Reflectance Spectrophotometry
Cell Count/Differential
Use for assessment of multiple sclerosis
Detect unique IgG oligoclonal bands in CSF in conjunction with a matched serum specimen
Preferred test is oligoclonal band profile testing
Qualitative Isoelectric Focusing/Electrophoresis
Preferred test is oligoclonal band profile testing
Index test aids in workup of suspected multiple sclerosis
Quantitative Immunoturbidimetry
Medical Experts
Slev

References
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Matutes E. Adult T-cell leukaemia/lymphoma. J Clin Pathol. 2007;60(12):1373-1377.
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Morrison BJ, Labo N, Miley WJ, et al. Serodiagnosis for tumor viruses. Semin Oncol. 2015;42(2):191-206.
Reflex pattern: if HTLV-I/II screen is repeatedly reactive, then confirmation testing by Western blot will be added