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

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
    • Sarcoidosis
    • Sjögren syndrome
    • Systemic lupus erythematosus
  • 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