Human T-Lymphotropic Virus Types I, II - HTLV I, II

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.

Tabs Content

Clinical Overview

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

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
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
- Malignant
  - Bony or epidural metastases
  - Primary intra/extra dural tumor
- Nutritional
  - B12 deficiency
  - Copper overload
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
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 Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Human T-Lymphotropic Virus (HTLV) Types I/II Antibodies by ELISA with Reflex to HTLV-I/II Confirmation by Western Blot 0051164
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Qualitative Western Blot

Recommended Use

Screen for antibodies to HTLV-I and -II

Reflex pattern – if HTLV-I/II screen is repeatedly reactive, then confirmation testing by Western blot will be added

Limitations

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

Human T-Lymphotropic Virus Types I/II DNA, Qualitative Real-Time PCR 2003075
Method: Real-Time Polymerase Chain Reaction

Recommended Use

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

Human T-Lymphotropic Virus Types I/II Antibodies, Western Blot 0020642
Method: Qualitative Western Blot

Recommended Use

Confirm antibody test results for a positive screening test (HTLV-I/II)

Limitations

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

Leukemia/Lymphoma Phenotyping by Flow Cytometry 2008003
Method: Flow Cytometry

Recommended Use

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

Antigens included

T cell: CD1, CD2, CD3, CD4, CD5, CD7, CD8, TCR α-β, TCR γ-δ, cytoplasmic CD3

B cell: CD10, CD19, CD20, CD22, CD23, CD103, kappa, lambda, FMC7, 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, ALK-1, CD123, CD138, CD200, CD26, CD45

Medical Experts

Slev, Patricia R., PhD, Laboratory Section Chief, Immunology, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009; 27(3): 453-9. PubMed

General References

Gonçalves DU, Proietti FA, Ribas JG, Araújo MG, Pinheiro SR, Guedes AC, Carneiro-Proietti AB. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin Microbiol Rev. 2010; 23(3): 577-89. PubMed

Matutes E. Adult T-cell leukaemia/lymphoma. J Clin Pathol. 2007; 60(12): 1373-7. PubMed

Morrison BJ, Labo N, Miley WJ, Whitby D. Serodiagnosis for tumor viruses. Semin Oncol. 2015; 42(2): 191-206. PubMed

Qayyum S, Choi JK. Adult T-cell leukemia/lymphoma. Arch Pathol Lab Med. 2014; 138(2): 282-6. PubMed

Román GC. Tropical myelopathies. Handb Clin Neurol. 2014; 121: 1521-48. PubMed

Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. 1991; 79(3): 428-37. PubMed

Taylor G. Molecular aspects of HTLV-I infection and adult T-cell leukaemia/lymphoma. J Clin Pathol. 2007; 60(12): 1392-6. PubMed

Testing Algorithms

Human T-Lymphotropic Virus Types I and II Testing Algorithm

Read more about Human T-Lymphotropic Virus Types I and II Testing Algorithm

Last Update: July 2018

Human T-Lymphotropic Virus Types I, II - HTLV I, II

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Imaging Studies

Prognosis

Differential Diagnosis

Background

Epidemiology

Organism

Risk Factors

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Human T-Lymphotropic Virus Types I and II Testing Algorithm

ARUP Laboratories

ARUP Websites

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	Human T-Lymphotropic Virus Types I, II - HTLV I, II. ARUP Consult^©. Retrieved February 20, 2019, from: https://arupconsult.com/content/human-t-lymphotropic-virus-types-i-ii