Human T-Cell Lymphotropic Virus Type 1 Infection

AUTHORS:
Brendan Lindgren, DO¹ • Manasi Sejpal, MD¹ • Samir C. Patel, MD¹ • Sandeep A. Gandhi, MD^1,2 • Kaushik Manthani, DO¹

AFFILIATIONS:
¹Peconic Bay Medical Center, Northwell Health, Riverhead, New York
²New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York

CITATION:
Lindgren B, Sejpal M, Patel SC, Gandhi SA, Manthani K. Human T-cell lymphotropic virus type 1 infection. Consultant. 2020;60(11):29-32. doi:10.25270/con.2020.06.00006

Received February 12, 2020. Accepted May 15, 2020.

DISCLOSURES:
The authors report no relevant financial relationships.

CORRESPONDENCE:
Sandeep A. Gandhi, MD, 200 Hawkins Ave #1362, Ronkonkoma, NY 11779 (sanganmd@gmail.com)

A 50-year-old man presented to the emergency department (ED) with intermittent chest discomfort for 8 days that had been associated with dyspnea and palpitations. He denied any exacerbating or relieving factors, syncope, edema, cough, or recent illnesses.

His only pertinent medical history was hypertension, but he had not been adherent to prescribed regimens of hydralazine and metoprolol. He had no previous surgical history, no history of smoking or illicit drug use, and only occasionally consumed alcohol.

On arrival, his blood pressure was 200/100 mm Hg, and his initial electrocardiography results showed sinus tachycardia (114 beats/min) with left ventricular hypertrophy and ST-segment elevation in the precordial leads, possibly secondary to repolarization abnormalities.

He underwent urgent heart catheterization, which revealed a hyperdynamic left ventricle with an ejection fraction of 75%, a significant gradient from the left ventricle to aortic outflow, and a spike and dome appearance consistent with hypertrophic obstructive cardiomyopathy. Coronary angiography revealed 50% stenosis of the right postural lateral segment with otherwise minor luminal irregularities. Computed tomography (CT) scans of the chest, abdomen, and pelvis revealed splenomegaly with diffuse lymphadenopathy (bilateral axillary, mediastinal, and mesenteric lymph nodes) and sclerotic lesions of the left iliac bones (Figure 1).

Figure 1. CT of the chest, abdomen, and pelvis without contrast, coronal view. The image on the left shows multiple, enlarged bilateral axillary lymphadenopathy (arrows) and splenomegaly measuring 14.5 cm in diameter. The image on the right shows small, patchy, sclerotic lesions consistent with bony metastasis (arrows).

An excisional lymph node biopsy was performed, and his severe hypercalcemia was successfully treated with intravenous fluids, calcitonin, and pamidronate. Outpatient follow up with an oncologist was planned for surveillance of hypercalcemia, review of biopsy results, and initiation of treatment based on pathology.

The man returned to the ED 10 days later with lethargy, confusion, and profound lower-extremity weakness with a wide-based gait. CT scans of the chest revealed moderate pericardial effusion with bilateral ground-glass opacities consistent with pulmonary edema (Figure 2). A cardiology consultant recommended avoiding diuresis and instead planned to perform a pericardial window.

Figure 2. CT of the chest without contrast, transverse view. The top image above shows bilateral ground-glass opacities in the upper lobes, consistent with pulmonary edema. The bottom image shows a moderate pericardial effusion.

Infection with human T-cell lymphotropic virus type 1 (HTLV-1) was confirmed via blood test, and results of the left axillary lymph node biopsy performed at the previous admission were consistent with adult T-cell lymphoma/leukemia (ATL). The patient’s symptoms improved with hemodialysis for hypercalcemia and an outpatient regimen of denosumab as recommended by an oncology consultant. The patient was eventually transferred for inpatient chemotherapy with the brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) regimen.

HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) was suspected in addition to ATL based on the patient’s lower-extremity weakness and wide-based gait. Based on infectious disease specialist recommendations, acyclovir was started as an anti-inflammatory treatment (not for its antiviral effects).

DISCUSSION

HTLV-1 was the first human retrovirus to be discovered, by Robert C. Gallo, MD, and his team in 1980.¹ This was a significant event, not only because of the discovery of HTLV-1 itself, but also because it paved the way for the discovery of future retroviruses. During the initial outbreak of AIDS in the early 1980s, Gallo correctly postulated that a similar retrovirus could be responsible.² Over the next 3 years, Gallo and his group isolated HTLV-II and “HTLV-III” (which is now known as HIV).³

Although HTLV-1 and HIV are often categorized together as the most significant pathologic human retroviruses, significant differences ultimately lead to different symptoms and different response to treatment. One of the most significant differences is how either virus affects CD4 T cells. While HIV infection leads to the destruction of CD4 T cells, HTLV-1 infection immortalizes them.³ Interestingly, Gallo and his group discovered HIV in a cell that was coinfected with HTLV-1, challenging the widely held “viral interference” belief that a cell infected with a retrovirus would resist superinfection with another virus.³ Researchers would use this knowledge to immortalize CD4 T cells infected with HIV in order to better study the virus.³

HTLV-1 is estimated to affect 5 million to 10 million humans worldwide,⁴ although many believe that this estimate may be an underestimation, because systematic testing is lacking in many parts of the world. Highly endemic areas include Japan, sub-Saharan Africa, the Caribbean islands, and South America (especially Brazil, Colombia, Chile, and Peru).⁴ HTLV-1 is predominantly spread through prolonged breastfeeding,⁵ unprotected sexual intercourse,⁶ and contamination of blood products.⁷ It is possibly the most oncogenic virus.⁸ Although most carriers are asymptomatic, it can cause two fatal diseases, ATL and HAM/TSP.

ATL is a peripheral T-cell neoplasm associated with HTLV-1,⁹ and it is seen in 2% to 4% of those infected with the virus.¹⁰ Symptoms may vary considerably but include abdominal pain, ascites, diarrhea, jaundice, pleural effusion, cough, sputum, fever, unconsciousness, and opportunistic infections. ATL can be further classified based on lymphadenopathy, splenomegaly, hepatomegaly, hypercalcemia, skin lesions, and pulmonary lesions. The 4 classifications are acute, lymphoma, chronic, and smoldering. Acute and lymphoma have median survival rates of 8.3 and 10.6 months, respectively, while chronic and smoldering have median survival rate of 31.5 and 55.0 months, respectively.¹¹ ATL usually develops after a 3- to 5-decade latency period and is rarely seen in those infected during adulthood.³ Only 20% to 25% of HTLV-1 infections are perinatal.³ So the true risk of ATL from perinatal HTLV-1 infection has been estimated to be as high as 25%,¹² which would exceed even the association between tobacco smoking and lung cancer (16%).¹³

HAM/TSP primarily affects the spinal cord and presents similarly to primary progressive multiple sclerosis (PPMS). The first symptoms are usually gait disturbance, tendency to fall, lower-extremity weakness (usually with preservation of upper-extremity strength), back pain, bowel and bladder dysfunction, hyperreflexia, and/or sexual dysfunction.¹⁴ In contrast with ATL, HAM/TSP usually develops after an infection in adulthood secondary to blood transfusion or organ transplantation.³ While most countries screen blood for HTLV-1, many countries, including the United States, do not screen organ donors for HTLV-1. While the risk of HAM/TSP is as low as 0.3% in perinatal infections, Yamano and colleagues’ studies have indicated that the risk is close to 10% in posttransplant cases.³ Additionally, while HAM/TSP usually manifests over several decades in perinatal infections, it can lead to morbidity in less than 5 years in posttransplant cases.³ These symptoms usually develop insidiously but also can develop abruptly over a few weeks.¹⁴ Physical examination findings can include spastic gait, lower-extremity weakness (usually worse proximally), and hyperreflexia.

Diagnosing HAM/TSP according to World Health Organization guidelines is a 4-step process. First, the patient must show the clinical signs mentioned above, followed by serologic confirmation of HTLV-1 (enzyme-linked immunosorbent assay followed by western blot confirmation; polymerase chain reaction testing may be done if western blot results are indeterminate). The final 2 steps (which were not done in this patient before transfer for inpatient chemotherapy) include cerebrospinal fluid (CSF) detection of anti–HTLV-1 antibodies and the exclusion of other disorders that present similarly.

The differential diagnosis for HAM/TSP includes PPMS, neuromyelitis optica (NMO), spinal cord compression, transverse myelitis, collagen vascular disease, Sjögren syndrome, hereditary spastic paraparesis, primary lateral sclerosis, vitamin B₁₂ and folate deficiency, HIV-associated vacuolar myelopathy, neurosyphilis, and Lyme disease.¹⁴ Quick diagnosis or exclusion of NMO is important, and NMO can confidently be assumed to be the diagnosis if optic neuritis and anti–aquaporin-4 antibodies are present, while their absence would be more supportive of rapidly progressing HAM/TSP.¹⁴ The most challenging diagnosis to exclude is PPMS, given the fact that their clinical presentation is indistinguishable. The mere presence of HTLV-1 does not necessarily mean that it is the source of the neurologic symptoms. Recent studies suggest that a useful distinguishing factor is that in HAM/TSP, the proviral load in the CSF is usually twice as high as the load in the peripheral blood mononuclear cells, while the ratio is usually lower in asymptomatic carriers.¹⁵

While ATL and HAM/TSP often receive the most attention, numerous other inflammatory disorders can happen as a result of HTLV-1 infection. These conditions are often overlooked and include uveitis, conjunctivitis, sicca syndrome, interstitial keratitis, pulmonary diseases, infective dermatitis, arthritis, myositis, Sjögren syndrome, Hashimoto thyroiditis, Graves disease, and polyneuropathies.¹⁰ HTLV-1–associated dermatitis is the most common manifestation in children. These conditions often occur in conjunction with ATL and HAM/TSP but may also occur in isolation.¹⁰ Additionally, patients with ATL may develop opportunistic infections or infestations such as with Strongyloides stercoralis, scabies, tuberculosis, and leprosy.¹⁶

Treatment of ATL remains an active area of research. Patients should be referred for clinical trials when possible. A number of regimens are currently under use for this condition: In CD30-positive cases (as in the case described above), the A+CHP regimen has been shown to provide median progression-free survival of 48.2 months¹⁷; alternatively dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is recommended in CD30-negative cases.¹⁸ The combination of zidovudine and interferon-alfa has been used with some success in various subtypes of ATL.¹⁹ Other recommended regimens include CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), and hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine. Second-line treatment options include single-agent brentuximab vedotin, lenalidomide, or mogamulizumab regimens.

At this time, HAM/TSP treatment is predominantly symptomatic. Corticosteroids had been reported to decelerate progression of the disease,²⁰ but study results since then have been mixed. There has never been a randomized clinical trial.²¹ Corticosteroids do not treat the underlying infection but may be of benefit due to their anti-inflammatory effects. Prednisone is often included in the treatment of ATL. Other treatments undergoing study include cyclosporine²² and mogamulizumab.²³

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