|Year : 2018 | Volume
| Issue : 4 | Page : 553-556
|Adult T-cell leukemia/lymphoma and acquired immunodeficiency syndrome - CD4+ T-cell malignancy in CD4+ T-cell deficient status: A paradox
Manu Goyal1, M Dinaker2, K Gayathri3
1 Department of Hematopathology, AmPath, Hyderabad, Telangana, India
2 Department of Medicine, Sunshine Hospital, Hyderabad, Telangana, India
3 Department of Hematopathology, Lifeline Tapadia Diagnostic Center, Hyderabad, Telangana, India
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|Date of Web Publication||10-Oct-2018|
| Abstract|| |
CD4 counts along with viral loads are important parameters in the monitoring of human immunodeficiency virus (HIV) infection. Human T-cell lymphotropic virus type I (HTLV-I) is known to be an etiological agent for adult T-cell leukemia/lymphoma (ATLL). Coinfection of HTLV-I and HIV is well known in regions with high seroprevalence, and there is no published data in the Indian scenario. We present an interesting case of occurrence of CD4+ T-cell proliferation in a known beta thalassemia major with acquired HIV seropositivity accompanied by simultaneously increasing CD4+ counts and viral loads. Further workup revealed ATLL with an underlying HTLV infection.
Keywords: Adult T-cell leukemia/lymphoma, CD4, human immunodeficiency virus, human T-cell lymphotropic virus type I, thalassemia, viral load
|How to cite this article:|
Goyal M, Dinaker M, Gayathri K. Adult T-cell leukemia/lymphoma and acquired immunodeficiency syndrome - CD4+ T-cell malignancy in CD4+ T-cell deficient status: A paradox. Indian J Pathol Microbiol 2018;61:553-6
|How to cite this URL:|
Goyal M, Dinaker M, Gayathri K. Adult T-cell leukemia/lymphoma and acquired immunodeficiency syndrome - CD4+ T-cell malignancy in CD4+ T-cell deficient status: A paradox. Indian J Pathol Microbiol [serial online] 2018 [cited 2019 Mar 21];61:553-6. Available from: http://www.ijpmonline.org/text.asp?2018/61/4/553/242962
| Introduction|| |
Human immunodeficiency virus (HIV) infection course and treatment response are best monitored by CD4 counts and viral loads. Acquired immunodeficiency syndrome (AIDS) is defined when CD4 cell count is < 200 cells/mm3 or with the occurrence of certain opportunistic disease. Individuals with only human T-cell lymphotropic virus type I (HTLV-I) infection tend to have higher CD4+ lymphocyte counts than HTLV-I seronegative controls due to increased proliferation of T-helper cells. The extent of the immunomodulatory effect of HTLV-I in HIV-infected persons is an unresolved issue; although, some studies have claimed that the former accelerates the HIV disease progression to AIDS.,, Our case is a patient of thalassemia major, who acquired HIV infection. On follow-up, he presented with an increasing viral load and paradoxical increase in CD4 counts, leading to subsequent work-up and the detection of adult T-cell leukemia/lymphoma (ATLL) due to HTLV-1 co-infection, a rare association.
| Case Report|| |
A 22-year-old male patient presented with severe breathlessness for the past 2 months. He was a known case of thalassemia major diagnosed at the age of 3 years. He was transfusion-dependent and received periodical blood transfusions with subsequent iron chelation. At the age of 10 years, he was detected to have acquired retroviral infection (HIV-1) for which he received zidovudine-based antiretroviral therapy for more than a decade. The therapy was discontinued 22 months before this presentation due to the development of severe peripheral neuropathy. When evaluated for breathlessness, his chest radiograph showed bilateral ground-glass opacity suggestive of interstitial fibrosis. Computed tomography scan revealed consolidation in right lung with few lung cysts. There were ill-defined nodules in left lung with ground-glass opacity bilaterally. There was massive hepatosplenomegaly. Bronchial wash evaluation depicted cysts of Pneumocystis jirovicii. He was given trimethoprim-sulfamethoxazole combination therapy and was oxygen-dependent. His CD4 counts and viral load were monitored regularly. The patient was found to have increasing CD4 counts with simultaneously rising viral loads [Table 1].
|Table 1: Serial CD3, CD4, CD8 subset evaluation and correlation with viral loads|
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His latest CD4 counts were evaluated using three-color flowcytometry using Dry T Stat-CD3/CD4/CD8 kit (ReaMetrix, India). The sample was processed using the lyse-no-wash technique. The sample was acquired on single laser three color flowcytometer-FACS Scan (BD Biosciences, San Jose, CA, USA). The sample was acquired until 3000 beads were counted. The data was analyzed using Cell Quest Pro software version 9.2.2. When the scatter plots of CD3 and side scatter were analyzed, it was found that there were two subsets of CD3 positive populations with slight variation in the intensity, the two populations separated arbitrarily. The brighter CD3 positive population when gated revealed the total CD3, CD3+ CD4+, and CD3+ CD8+ counts of 1850, 824, and 943 cells/mm3, respectively, with CD4:CD8 ratio of 0.87. The dimmer population when gated revealed CD3, CD3+ CD4+, and CD3+ CD8+ counts of 3467, 3375, and 65 cells/mm3, respectively, with CD4: CD8 ratio of 51.92.
The peripheral smear revealed atypical lymphoid cells. The cells were around two times the size of mature lymphocyte and had a moderate amount of cytoplasm. The nuclei were round with some showing indentations and convolutions. There were few flower cells [Figure 1]a. The peripheral blood sample was evaluated for flow cytometric analysis. The sample was processed using the lyse-wash technique according to the standard guidelines. The sample was analyzed and revealed dim CD3 positive population expressed bright CD45, CD4, CD5, CD2, and moderate CD25 [Figure 1]b. These cells were lacking expression(s) of CD7, CD8, CD1a, CD56, CD19, CD10, and CD34. Bone marrow aspirate and biopsy revealed infiltrates of similar cells.
|Figure 1: (a) Peripheral smear showing atypical medium sized lymphoid cell showing deeply basophilic cytoplasm and polylobated nucleus– flower cell (Leishman, original magnification, ×1000). (b) The abnormal lymphoid cells (population marked in red) show dim CD3 expression, brighter CD5, loss of CD7, and gain of CD25. These show CD4 clonal proliferation as compared to normal T-cells (population marked in green) that show polymorphous CD4 and CD8 positive populations. Both populations have similar CD2 expression and CD56 is negative. CD45 expression was bright in both and CD34, CD1a, CD19 and CD10 were noncontributory (not depicted in the above image)|
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The serology was positive for HTLV-I/II antibodies by enzyme immunoassay. T-cell gene rearrangement studies on the blood, using the DNA polymerase chain reaction, detected rearrangement of T-cell receptor. Based on all the available data, a final diagnosis of adult T-cell lymphoma/leukemia with Pneumocystis jirovicii infestation in a treated case of AIDS with underlying beta-thalassemia was rendered. Bilateral lung opacity could be due to either the infection or the lymphoma infiltrates. The cause for massive hepatosplenomegaly may be attributed to lymphoid cell infiltrates with underlying thalassemia. The patient's condition rapidly deteriorated and he succumbed.
| Discussion|| |
HTLV-I is closely related to HTLV-II, and both viruses are cross-reactive; whereas, they are remotely related to HIV with no cross-reactivity. While HTLV-I is associated with ATLL and tropical spastic paraparesis/HTLV-I-associated myelopathy, HTLV-II has not been definitively linked to human disease. HTLV-I is endemic in Japan, with a high incidence of detection in west Africa, Carribeans, and in areas where people from these origins have migrated to. Seroprevalence studies in the United States, Europe, and many developing countries barring India have demonstrated a high frequency of HTLV-I/II coinfection among individuals seropositive for HIV. In India, the seroprevalence of HTLV-I/II is low, and coinfection with HIV is not known to the best of our knowledge.
The effect of coinfection of HIV and HTLV-I on CD4+ lymphocyte counts is also unknown. Some studies have shown an increase in CD4+ cell count, thus masking an AIDS-defining event., The difference was seen in earlier stages (WHO stages 1 and 2) as compared to later stages (WHO stages 3 and 4). Higher CD4+ cell counts might be the result of stimuli produced by some HTLV-1 proteins, thus masking the apoptosis induced by the HIV-1 infection. However, when compared to single infection, the difference in the mean CD4+ percentage was not statistically significant. Therefore, the role of CD4 as a surrogate marker of progression to AIDS in patients with such coinfections is limited.,, In the present case, the paradoxical increase in CD4 counts in stage 4 of HIV infection lead to the subsequent detection of HTLV-I infection.
HIV has a propensity to destroy CD4 cells specifically, and on the other hand, HTLV-I triggers proliferation of CD4 cells. It would be interesting to understand how these two opposites function in tandem to generate a clonal T-cell as seen in our case. Current understanding of subset analysis of T-cells shows that naïve CD4+ T-cells (Tn) develop into memory T-cell (Tm), effector T-cell (Te), or the T-regulatory cells (Treg). There is evidence that the HIV-infected cells are predominantly the Tm and to some extent Tn and the CD8+ T-memory cells. Treg cells maintain T-cell tolerance to self-antigens in the periphery, avoid the development of autoimmune disorders and can suppress T-cell responses to foreign pathogens, including viruses such as HIV. Some studies show that the subsets are selectively preserved or depleted during HIV infection that provides some insight into disease progression. Dunham et al., 2008 have shown that there was a drop in Tn, and Tm with a rise in Te, while Treg count was usually conserved. On the other hand, the mechanisms for the spontaneous T-cell proliferation associated with HTLV-I infection appears to differ for HTLV-I-infected cells and HTLV-I uninfected cells. The infected cells express interleukin 2 (IL-2) receptors/CD25 and IL 6 but do not secrete IL-2. The uninfected autologous T-cells are activated by a mechanism that requires direct cell-to-cell contact and can be inhibited by anti-IL-2 antibodies. ATLL, a T-cell neoplasm, is postulated to arise from Treg that are FOXP3+. The selective preservation and proliferation of Treg population due to HTLV-I infection could explain the possible pathogenesis in our case.
HTLV-I is transmitted mainly through transfusion of infected blood and cellular blood products, intravenous drug abuse, perinatally, and sexually. HTLV-I antibody prevalence varies between <2% and >18% among apparently healthy controls in various countries. Approximately one in 4,000 blood donors in the United States is infected with HTLV-I. Hence, the prevalence of the virus is significantly higher among the high-risk group subjects and in specific geographic areas. The seroprevalence of HIV is also high in these populations, yet little is known about the consequences of coinfection with HTLV-I and HIV. The seroprevalence of HTLV-I/II in healthy donors in India is shown to be 0.18%. However, the incidence of HIV and HTLV coinfection in the Indian scenario is unknown.
It is highly possible that in our case is that the patient would have acquired both HIV and HTLV-I infection through the blood transfusion, at a time when HIV screening was not as sensitive or stringent as is today. Even today, HTLV-I screening is not done routinely in Indian blood banks due to the low incidence, that is acceptable, based on the reported occurrence. There is, however, a need to reconsider the screening strategies for what are considered uncommon occurrences; as illustrated by our case.
| Conclusion|| |
HTLV-1 and HIV coinfection can lead to varied and complex clinical presentations with unusual findings and complications. The laboratory parameters can provide vital insights into the underlying pathology and transformation. Unusual and unexpected laboratory results in the course of management warrant closer monitoring and additional relevant studies for better understanding. The need for HTLV-1 screening is to be evaluated in our population of blood donors.
We sincerely thank Dr. R.S. Tapadia, Lifeline Tapadia Diagnostic Center for providing financial support to perform additional tests for confirmation of the diagnosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Marsh BJ. Coinfection with human T lymphotropic virus type I and human immunodeficiency virus. J Infect Dis 1997;176:543-5.
Harrison LH, Quinn TC, Schechter M. Human T cell lymphotropic virus type I does not increase human immunodeficiency virus viral load in vivo
. J Infect Dis 1997;175:438-40.
Cleghorn FR, Blattner WA. Does human T-cell lymphotropic virus type I and human immunodeficiency virus type 1 coinfection accelerate acquired immunodeficiency syndrome? The jury is still out. Arch Intern Med 1992;152:1372-3.
Ohshima K, Jaffe ES, Kikuchi M. Adult T-cell leukaemia/lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
., editors. WHO Classifications of Tumours of Haematopoietic and Lymphoid Tissues. 4th
ed. Lyon: PA: IARC; 2008. p. 281-4.
Kumar H, Gupta PK. Is seroprevalence of HTLV-I/II among blood donors in India relevant? Indian J Pathol Microbiol 2006;49:532-4.
] [Full text]
Scapellato PG, Bottaro E, Brieschke MT, Scapellato JL, Dato A, Intile AD, et al.
CD4 cell count among HIV-infected patients with an AIDS-defining disease: Higher count in patients coinfected than in those not coinfected with human T-cell lymphotropic virus type I. J Acquir Immune Defic Syndr 2003;33:279-80.
Schechter M, Harrison LH, Halsey NA, Trade G, Santino M, Moulton LH, et al.
Coinfection with human T-cell lymphotropic virus type I and HIV in Brazil. Impact on markers of HIV disease progression. JAMA 1994;271:353-7.
Moon HS, Yang JS. Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells. Mol Cells 2006;21:7-20.
Fantry L, De Jonge E, Auwaerter PG, Lederman HM. Immunodeficiency and elevated CD4 T lymphocyte counts in two patients coinfected with human immunodeficiency virus and human lymphotropic virus type I. Clin Infect Dis 1995;21:1466-8.
Nadler JP, Bach MC, Godofsky E. Management of coinfection with human immunodeficiency virus and human T-cell lymphotropic virus type I. Clin Infect Dis 1996;23:415.
Dunham RM, Cervasi B, Brenchley JM, Albrecht H, Weintrob A, Sumpter B, et al.
CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection. J Immunol 2008;180:5582-92.
Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, et al.
T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo
: Implications for HIV pathogenesis. J Virol 2004;78:1160-8.
Nixon DF, Aandahl EM, Michaëlsson J. CD4+ CD25+regulatory T cells in HIV infection. Microbes Infect 2005;7:1063-5.
Fathalla SE, Al-Jama AA, Al-Sheikh IH, Islam SI. Seroepidemiological prevalence of human T-cell lymphotropic virus type I (HTLV-I) among healthy blood donors in Eastern Saudi Arabia. Ann Saudi Med 1998;18:366-7.
Khabbaz RF, Onorato IM, Cannon RO, Hartley TM, Roberts B, Hosein B, et al.
Seroprevalence of HTLV-1 and HTLV-2 among intravenous drug users and persons in clinics for sexually transmitted diseases. N Engl J Med 1992;326:375-80.
Department of Hematopathology, Ampath, AOI and Citizens Hospitals, Serilingampally, Nallagandla, Hyderabad - 500 019, Telangana
Source of Support: None, Conflict of Interest: None
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