HTLV-1, ATLL, refractory hypercalcaemia and HIV-1 co-infection

HTLV-1, ATLL, refractory hypercalcaemia and HIV-1 co-infection Adult T-cell lymphoma/leukemia (ATLL) is a rare tumour of T-lymphocytes that is associated with human T-lymphotrophic virus type 1 (HTLV-1) infection as well as severe/refractory hypercalcaemia. Human immunodefficiency virus type 1 (HIV-1) infected individuals are at increased risk of acquiring co-infection with HTLV-1. We present the case of a 37 -year -old HIV-1 positive and antiretroviral therapy naive woman who was admitted to the ICU with delirium, a generalised maculopapular rash, severe hypercalcaemia of 4.48 mmol/L (normal < 2.7 mmol/L) and a positive HTLV-1 serology. The diagnosis of ATLL was confirmed on biopsy. Her hypercalcaemic state proved refractory to conventional therapy, but was rapidly corrected with a modified haemodialysis technique using a dialysate with a low low-calcium concentration. individuals residing in HIV-1 seroprevalent regions such as INTRODUCTION sub-Saharan Africa is unknown, it is likely relatively higher. We Human T-lymphotropic virus type 1 (HTLV-1), is an oncogenic present a case of severe/refractory hypercalcaemia in an adult virus that was first isolated and described in 1980, although it patient with ATLL and HTLV-1/HIV-1 co-infection. has likely been a pathogen in humans since ancient times [1]. Severe/refractory hypercalcaemia is a common presenting fea- CASE REPORT ture in individuals with occult adult T-cell lymphoma/leukae- mia (ATLL), a malignancy of mature CD4 T-lymphocytes that A 37-year-old HIV-1 positive, antiretroviral therapy naive woman invariably occurs in individuals with underlying HTLV-1 infec- was admitted to the ICU with a history of a generalized maculo- tion [2]. HTLV-1 and human immunodeficiency virus type 1 papular rash, joint pains, pyrexia, fatigue and delirium. She had (HIV-1) are both retroviruses that infect CD4 lymphocytes and been diagnosed with HIV-1 infection in 2006 and as per local also share similar routes of transmission [3]. The prevalence of guidelines at the time was never initiated on antiretroviral therapy HTLV-1 infection is reportedly higher amongst HIV-1 positive as her CD4 lymphocyte count had always been >500 cells/μlat than HIV-1 negative individuals [4]. According to the latest regular clinic follow up. On examination, she appeared ill with a UNAIDS global update, there are 36.7 million people living with pyrexia of 39.1°C and a generalized maculopapular rash (Fig. 1). HIV around the world, with 2.1 million new infections in the Her knee, elbow and ankle joints were markedly swollen. She was year 2015 [5]. Although the prevalence of ATLL amongst also found to have axillary and inguinal lymphadenopathy, a 4 cm Received: July 26, 2017. Revised: October 10, 2017. Accepted: October 25, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018 HTLV-1, ATLL, refractory hypercalcaemia 19 DISCUSSION The tetrad presentation of ATLL, HTLV-1, severe/refractory hypercalcaemia and HIV-1 is likely underreported, mostly due to the fact that HTLV-1 is seldom considered for investigation in HIV-1 infected individuals [4]. Although a handful of case series and case reports describing the presentation of HTLV-1, ATLL and hypercalcaemia have been reported in the literature [2, 6], the prevalence of this presentation in HIV co-infected individuals is not known. Eastern and Southern African countries alone house 19 mil- lion individuals with HIV infection, which is more than half the global HIV burden [5]. Various studies have reported higher pre- valence’s of HTLV-1 co-infection amongst HIV-1 positive indivi- duals with a co-prevalence of both organisms in up to 28% of individuals with HIV infection [4, 7]. Although most individuals with HTLV-1 infection will remain asymptomatic throughout their life, it is estimated that <5% will progress to develop ATLL [8]. Severe/refractory hyper- calcaemia is frequently the presenting feature in up to 70% of individuals with occult ATLL and has also been associated with early mortality [9]. The underlying mechanisms responsible for ATLL associated hypercalcaemia include an over-expression of receptor activator of nuclear factor kappa B ligand (RANKL), Figure 1: maculopapular rash on right forearm. The rash was diffuse and increase in serum macrophage colony-stimulating factor (M-CSF) involved the entire body levels, bony infiltration of the malignancy itself and secretion of PTH-related peptide (PTH-rP) by the tumour [10]. Similar to our finding, other case reports and patient series splenomegaly but no hepatomegaly. Except for features in keeping have shown that the stepwise implementation of conventional with delirium, no other abnormal neurological signs were noted. calcium lowering therapy including saline dieresis and the On this admission she had a CD4 cell count of 616 cells/μl, a HIV administration of furosemide, glucocorticosteroids or intraven- viral load of 102 000 copies/mL and her HTLV-1 serology also ous bisphosphonates are ineffective in correcting calcium levels tested strongly positive. Except for a markedly raised serum cal- [2]. In our patient, calcium levels were rapidly corrected with cium level of 4.48 mmol/L, the rest of her laboratory work-up haemodialysis using a low calcium concentrate dialysate (1 including full blood count, electrolytes, renal and liver function mmol/L). This also resulted in dramatic improvement of her deli- test, blood and urine culture, autoimmune screen, serum protein rious mental state. The medical literature is rather scant with electrophoresis, serum angiotensin converting enzyme (S-ACE), regards consensus guidelines on the use of haemodialysis in the parathyroid hormone (PTH) assay, beta-2 microglobulin, urinary management of refractory hypercalcaemia. Denosumab, a fully Bence-Jones protein, joint fluid analysis and a nasopharangeal humanized monoclonal antibody has recently shown promise in swab for the detection of respiratory viruses were unremark- the management of refractory hypercalcaemic states [11]. able. A full body CAT scan showed extensive lymphadenopathy In conclusion, in the HIV-1 infected individual presenting to in the axillary, inguinal, pelvic and para-aortic regions. Radio- the ICU with severe/refractory hypercalcaemia, occult HTLV-1 isotopic bone scanning showed increased uptake in the juxta- associated ATLL must be considered as part of the differential articular areas of the elbow and knee joints. Histology of a skin diagnosis. lesion biopsy showed a vasculitic infiltration of abnormal look- ing T cells, whilst lymph node biopsy and bone marrow aspir- ation and trephine specimens confirmed the diagnosis of acute CONFLICT OF INTEREST STATEMENT ATLL. Her hypercalcaemia initially proved refractory to stepwise The authors’ hereby certify that this submission is not under conventional calcium lowering therapy that included large vol- publication consideration elsewhere, and is free of conflict of ume saline diuresis (normal saline at 200 mL/h × 24 h, then interest. 120 mL/h × 48h), loop diuretics (80 mg of furosemide 12h × 3 days), corticosteroids (100 mg of hydrocortisone 8h × 3 days) and intravenous bisphosphonate therapy (4 mg of zolendronic acid FUNDING over 15 min × 1 dose). On the fifth day, due to a lack of improve- There is no source of funding to declare. ment in the degree of hypercalcaemia and her persistent delir- ium, she was initiated on a modified SLED (slow low efficiency haemodialysis) regimen with a low calcium (1 mmol/L) contain- ETHICAL APPROVAL ing dialysate. After receiving 4 h of SLED on Day 5 and the same Not required. on Day 6, her serum calcium level had corrected to within nor- mal limits and her delirious state had dramatically improved. Upon stabilization of her condition in the ICU, she was trans- CONSENT ferred to the oncology department where chemotherapy and combination antiretroviral therapy (zidovudine/lamivudine/efa- Informed consent was obtained from the patient to make use virenz) were initiated. Unfortunately she demised a month later of patient data and photographs/images for publication from chemotherapy associated neutropenia and septic shock. purposes. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018 20 A.E. Laher et al. 1-infected individuals in Abuja, Nigeria. Virology 2015;6: AUTHOR CONTIBUTION STATEMENTS 17–23. doi:10.4137/VRT.S35331. Laher A.E.: guarantor of the manuscript and responsible for 5. Unaids. Global AIDS Update 2016. 2016. http://www.unaids. drafting, writing, review and incorporating co-author feedback, org/sites/default/files/media_asset/global-AIDS-update-2016_ revision, and final approval of the submission. Motara F.: con- en.pdf (29 June 2017, date last accessed). tributed to the drafting, writing, review, revision and approval 6. Naik S, Kodali S, Agheli A, Dumlao T, Singh V, Plummer K, of the article. Moolla M.: contributed to the drafting, writing, et al. HTLV-1 adult T cell leukemia-lymphoma presenting review, revision and approval of the article. Ebrahim O.: con- with refractory hypercalcemia, cranial neuropathy and tributed to the writing, review, revision of the article for diagnosis by flow cytometry and cytogenetic findings. Blood important intellectual content, and approval of the article. 2015;110:3864. 7. Bessong PO, Mathomu LM. Seroprevalence of HTLV1/2, HSV1/2 and Toxoplasma gondii among chronic HIV-1 REFERENCES infected individuals in rural northeastern South Africa. Afr J 1. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo Microbiol Res 2010;4:2587–91. 8. Matutes E, Catovsky D Leukaemia, 3rd edn. Oxford: Blackwell RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cuta- Scientific Publications, 1998. 9. Hagler KT, Lynch JW. Paraneoplastic manifestations of neous T-cell lymphoma. Proc Natl Acad Sci USA 1980;77: 7415–9. lymphoma. Clin Lymphoma 2004;5:29–36. 10. Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, 2. Edwards CMB, Edwards SJE, Bhumbra RP, Chowdhury TA. Severe refractory hypercalcaemia in HTLV-1 infection. JR Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear Soc Med 2003;96:126–7. 3. Mazanderani AH, Ebrahim O. Progressive HIV infection factor kappaB ligand on adult T-cell leukemia cells. Blood 2002;99:634–40. doi:10.1182/blood.V99.2.634. in thepresenceof a raised CD4+ count: HIV/HTLV-1 co-infection. South African J HIV Med 2013;14:92–4. doi:10. 11. Diel IJ, Body J-J, Stopeck AT, Vadhan-Raj S, Spencer A, Steger G, et al. The role of denosumab in the prevention of 7196/SAJHIVMED.904. 4. Nasir IA, Ahmad AE, Emeribe AU, Shehu MS, Medugu JT, hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 2015;51:1467–75. Babayo A. Molecular detection and clinical implications of HTLV-1 infections among antiretroviral therapy-naïve HIV- doi:10.1016/j.ejca.2015.04.017. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

HTLV-1, ATLL, refractory hypercalcaemia and HIV-1 co-infection

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Abstract

Adult T-cell lymphoma/leukemia (ATLL) is a rare tumour of T-lymphocytes that is associated with human T-lymphotrophic virus type 1 (HTLV-1) infection as well as severe/refractory hypercalcaemia. Human immunodefficiency virus type 1 (HIV-1) infected individuals are at increased risk of acquiring co-infection with HTLV-1. We present the case of a 37 -year -old HIV-1 positive and antiretroviral therapy naive woman who was admitted to the ICU with delirium, a generalised maculopapular rash, severe hypercalcaemia of 4.48 mmol/L (normal < 2.7 mmol/L) and a positive HTLV-1 serology. The diagnosis of ATLL was confirmed on biopsy. Her hypercalcaemic state proved refractory to conventional therapy, but was rapidly corrected with a modified haemodialysis technique using a dialysate with a low low-calcium concentration. individuals residing in HIV-1 seroprevalent regions such as INTRODUCTION sub-Saharan Africa is unknown, it is likely relatively higher. We Human T-lymphotropic virus type 1 (HTLV-1), is an oncogenic present a case of severe/refractory hypercalcaemia in an adult virus that was first isolated and described in 1980, although it patient with ATLL and HTLV-1/HIV-1 co-infection. has likely been a pathogen in humans since ancient times [1]. Severe/refractory hypercalcaemia is a common presenting fea- CASE REPORT ture in individuals with occult adult T-cell lymphoma/leukae- mia (ATLL), a malignancy of mature CD4 T-lymphocytes that A 37-year-old HIV-1 positive, antiretroviral therapy naive woman invariably occurs in individuals with underlying HTLV-1 infec- was admitted to the ICU with a history of a generalized maculo- tion [2]. HTLV-1 and human immunodeficiency virus type 1 papular rash, joint pains, pyrexia, fatigue and delirium. She had (HIV-1) are both retroviruses that infect CD4 lymphocytes and been diagnosed with HIV-1 infection in 2006 and as per local also share similar routes of transmission [3]. The prevalence of guidelines at the time was never initiated on antiretroviral therapy HTLV-1 infection is reportedly higher amongst HIV-1 positive as her CD4 lymphocyte count had always been >500 cells/μlat than HIV-1 negative individuals [4]. According to the latest regular clinic follow up. On examination, she appeared ill with a UNAIDS global update, there are 36.7 million people living with pyrexia of 39.1°C and a generalized maculopapular rash (Fig. 1). HIV around the world, with 2.1 million new infections in the Her knee, elbow and ankle joints were markedly swollen. She was year 2015 [5]. Although the prevalence of ATLL amongst also found to have axillary and inguinal lymphadenopathy, a 4 cm Received: July 26, 2017. Revised: October 10, 2017. Accepted: October 25, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018 HTLV-1, ATLL, refractory hypercalcaemia 19 DISCUSSION The tetrad presentation of ATLL, HTLV-1, severe/refractory hypercalcaemia and HIV-1 is likely underreported, mostly due to the fact that HTLV-1 is seldom considered for investigation in HIV-1 infected individuals [4]. Although a handful of case series and case reports describing the presentation of HTLV-1, ATLL and hypercalcaemia have been reported in the literature [2, 6], the prevalence of this presentation in HIV co-infected individuals is not known. Eastern and Southern African countries alone house 19 mil- lion individuals with HIV infection, which is more than half the global HIV burden [5]. Various studies have reported higher pre- valence’s of HTLV-1 co-infection amongst HIV-1 positive indivi- duals with a co-prevalence of both organisms in up to 28% of individuals with HIV infection [4, 7]. Although most individuals with HTLV-1 infection will remain asymptomatic throughout their life, it is estimated that <5% will progress to develop ATLL [8]. Severe/refractory hyper- calcaemia is frequently the presenting feature in up to 70% of individuals with occult ATLL and has also been associated with early mortality [9]. The underlying mechanisms responsible for ATLL associated hypercalcaemia include an over-expression of receptor activator of nuclear factor kappa B ligand (RANKL), Figure 1: maculopapular rash on right forearm. The rash was diffuse and increase in serum macrophage colony-stimulating factor (M-CSF) involved the entire body levels, bony infiltration of the malignancy itself and secretion of PTH-related peptide (PTH-rP) by the tumour [10]. Similar to our finding, other case reports and patient series splenomegaly but no hepatomegaly. Except for features in keeping have shown that the stepwise implementation of conventional with delirium, no other abnormal neurological signs were noted. calcium lowering therapy including saline dieresis and the On this admission she had a CD4 cell count of 616 cells/μl, a HIV administration of furosemide, glucocorticosteroids or intraven- viral load of 102 000 copies/mL and her HTLV-1 serology also ous bisphosphonates are ineffective in correcting calcium levels tested strongly positive. Except for a markedly raised serum cal- [2]. In our patient, calcium levels were rapidly corrected with cium level of 4.48 mmol/L, the rest of her laboratory work-up haemodialysis using a low calcium concentrate dialysate (1 including full blood count, electrolytes, renal and liver function mmol/L). This also resulted in dramatic improvement of her deli- test, blood and urine culture, autoimmune screen, serum protein rious mental state. The medical literature is rather scant with electrophoresis, serum angiotensin converting enzyme (S-ACE), regards consensus guidelines on the use of haemodialysis in the parathyroid hormone (PTH) assay, beta-2 microglobulin, urinary management of refractory hypercalcaemia. Denosumab, a fully Bence-Jones protein, joint fluid analysis and a nasopharangeal humanized monoclonal antibody has recently shown promise in swab for the detection of respiratory viruses were unremark- the management of refractory hypercalcaemic states [11]. able. A full body CAT scan showed extensive lymphadenopathy In conclusion, in the HIV-1 infected individual presenting to in the axillary, inguinal, pelvic and para-aortic regions. Radio- the ICU with severe/refractory hypercalcaemia, occult HTLV-1 isotopic bone scanning showed increased uptake in the juxta- associated ATLL must be considered as part of the differential articular areas of the elbow and knee joints. Histology of a skin diagnosis. lesion biopsy showed a vasculitic infiltration of abnormal look- ing T cells, whilst lymph node biopsy and bone marrow aspir- ation and trephine specimens confirmed the diagnosis of acute CONFLICT OF INTEREST STATEMENT ATLL. Her hypercalcaemia initially proved refractory to stepwise The authors’ hereby certify that this submission is not under conventional calcium lowering therapy that included large vol- publication consideration elsewhere, and is free of conflict of ume saline diuresis (normal saline at 200 mL/h × 24 h, then interest. 120 mL/h × 48h), loop diuretics (80 mg of furosemide 12h × 3 days), corticosteroids (100 mg of hydrocortisone 8h × 3 days) and intravenous bisphosphonate therapy (4 mg of zolendronic acid FUNDING over 15 min × 1 dose). On the fifth day, due to a lack of improve- There is no source of funding to declare. ment in the degree of hypercalcaemia and her persistent delir- ium, she was initiated on a modified SLED (slow low efficiency haemodialysis) regimen with a low calcium (1 mmol/L) contain- ETHICAL APPROVAL ing dialysate. After receiving 4 h of SLED on Day 5 and the same Not required. on Day 6, her serum calcium level had corrected to within nor- mal limits and her delirious state had dramatically improved. Upon stabilization of her condition in the ICU, she was trans- CONSENT ferred to the oncology department where chemotherapy and combination antiretroviral therapy (zidovudine/lamivudine/efa- Informed consent was obtained from the patient to make use virenz) were initiated. Unfortunately she demised a month later of patient data and photographs/images for publication from chemotherapy associated neutropenia and septic shock. purposes. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018 20 A.E. Laher et al. 1-infected individuals in Abuja, Nigeria. Virology 2015;6: AUTHOR CONTIBUTION STATEMENTS 17–23. doi:10.4137/VRT.S35331. Laher A.E.: guarantor of the manuscript and responsible for 5. Unaids. Global AIDS Update 2016. 2016. http://www.unaids. drafting, writing, review and incorporating co-author feedback, org/sites/default/files/media_asset/global-AIDS-update-2016_ revision, and final approval of the submission. Motara F.: con- en.pdf (29 June 2017, date last accessed). tributed to the drafting, writing, review, revision and approval 6. Naik S, Kodali S, Agheli A, Dumlao T, Singh V, Plummer K, of the article. Moolla M.: contributed to the drafting, writing, et al. HTLV-1 adult T cell leukemia-lymphoma presenting review, revision and approval of the article. Ebrahim O.: con- with refractory hypercalcemia, cranial neuropathy and tributed to the writing, review, revision of the article for diagnosis by flow cytometry and cytogenetic findings. Blood important intellectual content, and approval of the article. 2015;110:3864. 7. Bessong PO, Mathomu LM. Seroprevalence of HTLV1/2, HSV1/2 and Toxoplasma gondii among chronic HIV-1 REFERENCES infected individuals in rural northeastern South Africa. Afr J 1. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo Microbiol Res 2010;4:2587–91. 8. Matutes E, Catovsky D Leukaemia, 3rd edn. Oxford: Blackwell RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cuta- Scientific Publications, 1998. 9. Hagler KT, Lynch JW. Paraneoplastic manifestations of neous T-cell lymphoma. Proc Natl Acad Sci USA 1980;77: 7415–9. lymphoma. Clin Lymphoma 2004;5:29–36. 10. Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, 2. Edwards CMB, Edwards SJE, Bhumbra RP, Chowdhury TA. Severe refractory hypercalcaemia in HTLV-1 infection. JR Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression of receptor activator of nuclear Soc Med 2003;96:126–7. 3. Mazanderani AH, Ebrahim O. Progressive HIV infection factor kappaB ligand on adult T-cell leukemia cells. Blood 2002;99:634–40. doi:10.1182/blood.V99.2.634. in thepresenceof a raised CD4+ count: HIV/HTLV-1 co-infection. South African J HIV Med 2013;14:92–4. doi:10. 11. Diel IJ, Body J-J, Stopeck AT, Vadhan-Raj S, Spencer A, Steger G, et al. The role of denosumab in the prevention of 7196/SAJHIVMED.904. 4. Nasir IA, Ahmad AE, Emeribe AU, Shehu MS, Medugu JT, hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 2015;51:1467–75. Babayo A. Molecular detection and clinical implications of HTLV-1 infections among antiretroviral therapy-naïve HIV- doi:10.1016/j.ejca.2015.04.017. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx081/4812530 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Jan 1, 2018

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