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Gorgas Case 2023-06

History: A 61-year-old male patient presented with a 7-day history starting with headache and nausea. Five days before admission, he had one episode of bilious vomiting, accompanied by fever, abdominal pain, and malaise. Four days before admission, he presented persistent vomiting, worsening of the abdominal pain, hyporexia, and noticed abdominal distention, with persistence of the other symptoms. Two days before admission, he noted a decrease in urinary output and the vomiting led to oral intolerance. On the day of admission, he felt palpitations and noted a yellow tinge in his sclerae and decided to seek medical attention.

Epidemiology: Born in Huancayo, in the central highlands; has lived in San Juan de Lurigancho, in Lima, for the past twenty years. Works as a builder. Frequently travels to the jungle: traveled to Satipo (low jungle) for three days two months before admission; traveled to San Martín de Pangoa (low jungle) for one week and returned one week before admission. While traveling, he swam in rivers and stagnant waters.

Past medical history: Hypertension and hyperlipidemia diagnosed one year ago, currently receiving losartan 50mg bid irregularly. Heavy alcohol drinker from 17 years of age.

Physical Examination: BP 120/60 mmHg, HR 137 bpm, RR 22 rpm, T 36.6°C. Skin: Spider telangiectasias on chest, purpuric patches on left upper torso (6x5cm) and upper back (15x15cm). Pallor, jaundiced sclerae. Respiratory: bilaterally diminished breath sounds in lower thirds. CV: Tachycardic, regular rate and rhythm. Abdomen: Mildly distended. Liver palpable 2cm below right costal margin. Neuro: Disoriented in time and place. No focal or meningeal signs.

Laboratory: Hb 14.5 mg/dL, Hct 43%. WBC 100 540 (0% bands, 21% neutrophils, 7% lymphocytes, 61% atypical lymphocytes, 0% eosinophils, 0% basophils, 9% monocytes, 1% myelocytes, 1% metamyelocytes). Platelets 186 000. Glucose 87, creatinine 4.22, Na 128, K 4.36, Cl 85, Ca 10.4 mg/dL (8.4-10.2), ionized Ca 1.59 mmol/L (1.15-1.29). INR 1.21. Total bilirubin 6.24 (direct 4.01), alkaline phosphatase 1062, AST 365, ALT 231. HIV non-reactive, HBsAg negative, VDRL negative. CRP 12. Stool O&P is shown in Image A. Blood film is shown in Image B.

UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director

Diagnosis: Acute adult T-cell leukemia/lymphoma and strongyloidiasis in a patient with HTLV-1.

Discussion: A Stool O&P (Image A) was positive for Strongyloides stercoralis rhabditiform larvae. ELISA for Human T-lymphotropic virus (HTLV)-1/2 was positive. A peripheral blood smear revealed multiple flower cells (Image B), and a diagnosis of adult T-cell leukemia/lymphoma (ATLL) was made.

HTLV-1 is a human RNA virus of the Retroviridae family that is transmitted primarily through breastfeeding but can also be transmitted parenterally or through sexual intercourse. The risk of transmission via breastfeeding has been estimated to be between 16-30%¹, and increases with longer durations of breastfeeding. Our patient was breastfed for approximately one year. An extensive family history was taken; the patient’s father died of stomach cancer and his mother of complications of diabetes. There was no history of leukemia or neurological disease among his parents or six siblings, but he had a nephew that died at 12 years of age of acute leukemia. His family had never been tested for HTLV. His wife was tested after his diagnosis, she was also HTLV-1 positive. They have four children together, all breast-fed for at least 6 months and apparently healthy, but not yet tested for HTLV-1.

HTLV-1 has been associated with a host of pathologic entities. One of the most clinically significant ones is ATLL, a lymphoproliferative malignancy of mature CD4+ CD25+ T cells. Patients with HTLV-1 have a cumulative lifetime risk of developing ATLL of 2-5%, and ATL usually occurs 20-30 years after infection². Four clinical forms of ATLL have been described. The acute form accounts for more than half of patients, and presents aggressively, as was the case with our patient, with extensive involvement of multiple organ systems either due to direct leukemic infiltration or opportunistic infections. The lymphomatous form occurs in about 25% of cases and is less severe. About 20% of patients present with a chronic form, which is milder and has better survival rates. Finally, the smoldering form of ATL is the least common and least aggressive form. Patients require chemotherapeutic treatment, though there is no consensus on the optimal combination of agents, but mortality rates are still very elevated.

HTLV-1-associated myelopathy (HAM), also referred to as tropical spastic paraparesis (TSP), is the other well-recognized clinical entity associated with HTLV-1 (See: Case of the Week 2002-08). It affects less than 2% of HTLV-1 positive persons, and presents as a slowly progressive weakness with spasticity in both legs, which slowly progresses until patients require a wheelchair in a median of 21 years³. Though some cohort studies seem to suggest that ATLL and HAM follow different pathophysiological mechanisms and do not frequently co-occur in patients with HTLV-1, we have seen at our institution that a significant number of patients present with both pathologic entities. HTLV-1 has also been associated with Strongyloides stercoralis and Schistosoma mansoni infection. In particular, HTLV-1 infection has been linked to higher odds of S. stercoralis infection, higher risk of severe strongyloidiasis (e.g. hyperinfection), and higher rates of strongyloidiasis treatment failure⁴. Studies conducted at our institution found that HTLV-1/S. stercoralis coinfected patients had higher worm burdens, lower eosinophil counts and decreased antigen-driven production of IL-5, with an apparent increased regulatory T cell function⁵. The exact pathophysiological mechanism leading to higher risk of S. stercoralis or other parasitic dissemination in HTLV-1 patients is still not understood, though virus-mediated dysregulation of the immune system with reduction in the Th2 pattern immune response may explain the predisposition to helminthic infections. Severe strongyloidiasis should be treated with ivermectin 200mcg/kg per day for two weeks or until stool examination is negative for at least two weeks, to ensure the autoinfective cycle has stopped. Empiric antibiotic therapy against enteric gram-negative bacteria should also be considered in specific cases, as the migrating Strongyloides can carry parasites from the gut into the bloodstream.

HTLV-1 has also been linked to other infectious processes such as infective dermatitis, tuberculosis, superficial mycoses, and Norwegian scabies. In addition, it has been associated with increased odds of uveitis; rheumatologic disorders such as Sjögren’s syndrome, inflammatory arthritis, rheumatoid arthritis and fibromyalgia; pulmonary disorders such as lymphocytic alveolitis and bronchiectasis; and several forms of cancer other than ATLL, such as liver cancer, cervical cancer, and lymphoma⁶.

There is no treatment for asymptomatic infection with HTLV-1. Patients should be counseled to avoid breastfeeding, blood donation, and needle sharing and to practice safe sex in order to avoid transmission to others. There is no role for antiretroviral therapy in asymptomatic infection; however, the use of zidovudine and IFN-α has shown some benefit in patients with ATLL.

Our patient received daily doses of ivermectin until stool samples turned negative for Strongyloides and is currently undergoing chemotherapy with dose-adjusted EPOCH for ATLL. At our institution, we screen all family members of HTLV-1/2 positive patients for HTLV and conduct long-term follow up for early detection of complications.

References:
1. Hirata M, Hayashi J, Noguchi A, et al. The effects of breastfeeding and presence of antibody to p40tax protein of human T cell lymphotropic virus type-I on mother to child transmission. Int J Epidemiol. 1992;21(5):989-994. doi:10.1093/ije/21.5.989
2. Kondo T, Kono H, Miyamoto N, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer. 1989;43(6):1061-1064. doi:10.1002/ijc.2910430618
3. Yamano Y, Sato T. Clinical Pathophysiology of Human T-Lymphotropic Virus-Type 1-Associated Myelopathy/Tropical Spastic Paraparesis. Front Microbiol. 2012;3:389. doi:10.3389/fmicb.2012.00389
4. Ye L, Taylor GP, Rosadas C. Human T-Cell Lymphotropic Virus Type 1 and Strongyloides stercoralis Co-infection: A Systematic Review and Meta-Analysis. Frontiers in Medicine. 2022;9. Accessed March 6, 2023. https://www.frontiersin.org/articles/10.3389/fmed.2022.832430
5. Montes M, Sanchez C, Verdonck K, et al. Regulatory T Cell Expansion in HTLV-1 and Strongyloidiasis Co-infection Is Associated with Reduced IL-5 Responses to Strongyloides stercoralis Antigen. PLOS Neglected Tropical Diseases. 2009;3(6):e456. doi:10.1371/journal.pntd.0000456
6. Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. The Lancet Infectious Diseases. 2020;20(1):133-143. doi:10.1016/S1473-3099(19)30402-5