Human T-Lymphotropic Virus Types I, II

Indications for Testing

Clinical presentation of adult T-cell leukemia/lymphoma (ATLL) or HTLV-I associated myelopathy (HAM) in patient with risk factors (eg, IV drug use, multiple sex partners, residence in endemic area) or undiagnosed myopathy or myelopathy
ATLL subtypes and diagnostic criteria

Laboratory Testing

Required evaluation for ATLL (according to Shimoyama criteria, 1991)
- Peripheral blood smear – ATLL cells present
- HTLV-I testing
- HTLV-I antibody testing
  - HTLV-I and -II antibodies by EIA/Western blot is initial test
  - 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
  - Asymptomatic patients with HTLV-I antibodies
    - May be infected and should not donate blood
    - May not have ATLL or tropical spastic paraparesis (TSP) and may not develop ATLL, HAM or TSP
  - Proviral loads correlate with infectivity
- HTLV-I, II PCR – use to resolve untypable or indeterminate HTLV Western blot results when there is a strong suspicion of HTLV infection
CSF studies
- Protein – increased
- Cell differential – lymphocytic pleocytosis
- HTLV antibodies – positive
- Oligoclonal bands – positive
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

CT – recommend neck, thorax, abdomen and pelvis to exclude extranodal disease
Upper gastrointestinal endoscopy
Central nervous system evaluation by CT/MRI if neurologic signs evident

Prognosis

Poor prognosis risk factors
- Serum LD elevated
- Serum calcium elevated
- Age ≥40
- Three or more lesions
- Additional – thrombocytopenia, eosinophilia, high IL5, p53 or p16 deletion

Differential Diagnosis

HAM/TSP
- Amyotrophic lateral sclerosis
- HIV
- Multiple sclerosis
- Myopathies
  - Inflammatory myopathies
  - Genetic myopathies
- Myositis
- Paraneoplastic syndromes
- Polio
- Parkinson disease
ATLL

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 with HTLV-I-associated myelopathy (HAM).

Epidemiology

Prevalence – 15-20 million infected with HTLV-I worldwide
- Endemic in Japan, Caribbean countries and sub-Saharan Africa
Age – median is 50s
- HAM/TSP – 30s-40s
Sex
- ATLL – M>F
- HAM/TSP – M<F
Transmission
- Parenteral
- Sexual
Lifetime risk of disease if HTLV-I antibodies present is low
- ATLL – 1-5% even in countries with high prevalence of HTLV-I (eg, Japan)
- 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
Majority of human infections caused by subtype I
HTLV and AIDS
- HTLV-I does not cause AIDS
- Antibodies of HTLV-I have no relationship to antibodies of human immunodeficiency virus 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)
Suspicion of perinatal transmission
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 usually present 8-10 years before diagnosis
- Prominent weakness of lower extremities with severe spasticity
  - Upper extremity weakness rare
  - Mild sensory impairment
  - Hyperreflex 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

Tests generally appear in the order most useful for common clinical situations

Test name: Human T-Lymphotropic Virus Types I/II Antibodies with Reflex to HTLV I/II Confirmation

ARUP #: 0051164

Methodology: Qualitative Enzyme Immunoassay/Qualitative Western Blot

Use:

Screen for antibodies to HTLV-I and II

Limitations:

Assay should not be used for blood donor screening, associated re-entry protocols, or for screening human cell, tissues and cellular and tissue-based products

Test name: Human T-Lymphotropic Virus Types I/II DNA, Qualitative Real-Time PCR

ARUP #: 2003075

Methodology: Real-Time Polymerase Chain Reaction

Use:

Resolve untypable or indeterminate HTLV Western blot results when there is a strong suspicion of HTLV infection

Test name: Human T-Lymphotropic Virus Types I/II Antibodies, Western Blot

ARUP #: 0020642

Methodology: Qualitative Western Blot

Use:

Confirm antibody test results for a positive screening test (HTLV types I and II) performed in another lab

Follow-up:

If results are untypable or indeterminate, repeat test in 3 months

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Whole Blood)

ARUP #: 0096299

Methodology: Flow Cytometry

Use:

Use for whole blood specimens to identify tumor cell populations; aid in selection of appropriate therapy and assessment of clinical behavior and prognosis

T-cell antigens include CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR alpha-beta, TCR gamma-delta, cytoplasmic CD3

Other antigens include CD11c, CD16, CD25, CD30, CD34, CD38, CD41, CD42b, CD45, CD56, CD57, CD61, HLA-DR, glycophorin, TdT, bcl-2

Additional Tests Available

Test name: Lactate Dehydrogenase, Serum or Plasma

ARUP #: 0020006

Methodology: Quantitative Enzymatic

Comments:

Test name: Calcium, Serum or Plasma

ARUP #: 0020027

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Protein, Total, CSF