de Mendoza et al. BMC Infectious Diseases (2019) 19:706 https://doi.org/10.1186/s12879-019-4346-z RESEARCH ARTICLE Open Access HTLV-1 infection in solid organ transplant donors and recipients in Spain Carmen de Mendoza1,2, Lourdes Roc3, Rafael Benito4, Gabriel Reina5, José Manuel Ramos6, Cesar Gómez7, Antonio Aguilera8, Manuel Rodríguez-Iglesias9, Juan García-Costa10, Miriam Fernández-Alonso5, Vicente Soriano11* and on behalf of the Spanish HTLV Network Abstract Background: HTLV-1 infection is a neglected disease, despite infecting 10–15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. Methods: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. Results: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. Conclusion: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopathy. Keywords: HTLV-1, Transplantation, Screening, Tropical spastic paraparesis, Adult T-cell leukaemia, Immunosuppression * Correspondence: vicente.soriano@unir.net 11 UNIR Health Sciences School and Medical Centre, Calle Almansa 101, 28040 Madrid, Spain Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Mendoza et al. BMC Infectious Diseases (2019) 19:706 Page 2 of 5 Background Statistical analysis HTLV-1 infection is a neglected disease. As with other All numerical variables are reported as absolute values human retroviruses, i.e. HIV, acute infection is universally and percentages. Categorical variables were compared followed by long-lasting persistence of the virus. Clinical using χ2 or Fisher exact tests whereas non-categorical manifestations develop in roughly 10% of carriers lifelong, variables were compared using Student T-test or Mann- typically as subacute myelopathy which is known as trop- Whitney U tests. All analyses were 2-tailed and only p ical spastic paraparesis/HTLV-1-associated myelopathy values below 0.05 were considered as significant. All (TSP/HAM) [1] or a lymphoproliferative disorder named statistical analyses were performed using SPSS software adult T-cell leukaemia/lymphoma (ATLL) [2]. Screening version 16.0 (SPSS Inc., Chicago, IL). for HTLV antibodies is recommended in blood donors in some countries. Acknowledging a greater risk for develop- Results ing HTLV-1 associated illnesses due to immunosuppres- A total of 5751 individuals were tested for HTLV anti- sion [3], screening of transplant donors and recipients is bodies at 8 sites. Table 1 records the main characteris- widely being encouraged [4]. tics of the study population. Donors represented 2312 Spain is leading solid organ transplantation worldwide. (42.2%), of whom only 17 (0.3%) were living kidney do- With 47 million people, 5261 transplants were per- nors. The remaining 3439 (59.8%) were recipients. formed in 2017 (kidney 3269), liver (1247), lung (363) Males were predominant (59.7%). The median age was and heart (304). Overall it represents 20% of transplants 57-years old. Spaniards represented nearly 80%, being within the European Union. Until recently, the Spanish Latin Americans only 65 (1.1%) and Africans 101 law only recommended HTLV testing for persons with (1.8%). Overall, transplant recipients were more fre- high epidemiological risk of infection [5]. Herein, we quently male, younger, and native Spaniards than organ report the experience with universal testing of a large donors. population of donors and recipients of solid organ trans- Overall, 9 individuals were initially reactive for HTLV plants in Spain. antibodies. Table 2 summarizes the main characteristics of these patients. Six were donors and 3 were recipients. Using confirmatory tests (western blot and PCR), Method HTLV-1 was found in only two patients. Another three A nationwide network of hospitals/clinics/labs was set up were positive for HTLV-2. Two samples gave indeter- in Spain in 1989 and a national register of HTLV-1 cases minate results and another two were negative. works since then. Currently, more than 50 centres distrib- The two HTLV-1 positive cases were donors. Thus, uted across the Spanish geography belong to this group. the overall rate of HTLV-1 among solid transplant do- Further information on this network has been reported nors in our study was 0.09%. The first individual was a elsewhere [6]. All hospitals were invited to participate in 49-year old female, born in Colombia, diagnosed in the current study. Briefly, HTLV antibody screening using 2015, at the time she was assessed to be a kidney living chemiluminescence and/or ELISA of all solid organ donor. Before moving to the surgical procedure, she was donors and recipients attended since 2008 was retrospect- discharged as potential donor following knowledge of ively analyzed. her HTLV-1 seropositive status. Table 1 Main features of the study population Total Donors Recipients p No. (%) 5751 2312 (42.2%) a 3439 (59.8%) – Male gender (%) 3435 (59.7) 1234 (53.4) 2201 (64) < 0.001 Median age (IQR, years) 57 (45–66) 59 (45–71) 56 (45–65) < 0.001 Country of birth (%) Spain 4595 (79.9) 1383 (59.8) 3212 (93.4) < 0.001 Other EU countries 114 (2) 34 (1.5) 80 (2.3) – Africa 101 (1.8) 14 (0.6) 87 (2.5) < 0.05 Latin America 65 (1.1) 25 (1.1) 40 (1.2) – Asia 9 (0.2) 4 (0.2) 5 (0.1) – Unknown 867 (15.1) 851 (36.8) 15 (0.4) – a 17 (0.3%) donors were living kidney donors de Mendoza et al. BMC Infectious Diseases (2019) 19:706 Page 3 of 5 Table 2 Main features of HTLV-seroreactive individuals Case Year Donor or Recipient Gender Age range (years) Country of birth Confirmatory test 1 2010 donor female 35–40 Spain HTLV-2 2 2011 donor female 80–85 Spain negative 3 2011 recipient male 45–50 Spain indeterminate 4 2011 donor male 45–50 Spain HTLV-2 5 2015 donor male 35–40 Spain HTLV-1 6 2015 donor female 45–50 Colombia HTLV-1 7 2015 recipient male 45–50 Spain HTLV-2 8 2016 donor male 50–55 Spain negative 9 2017 recipient female 25–30 Colombia indeterminate The second HTLV-1 case was a 38-year old male, born immigration facilitated by strong cultural and ancestor in Spain, that died in 2015. Both kidneys were inadvert- links [6]. ently transplanted. TSP/HAM developed within 1 year Since the year 1988 there is a national register of in one recipient, despite antiretroviral prophylaxis HTLV-1 cases in Spain. A total of 369 cases had been re- attempted within the first weeks. The second recipient ported until December 2018. Most cases are concen- seroconverted for HTLV-1 but the kidney had to be trated around the largest urban areas (Madrid and removed soon due to rejection. Immunosuppression was Barcelona) where the greatest immigrant populations are stopped and to date, 3 years later, the patient remains in living. However, HTLV-1-infected persons have been dialysis but otherwise asymptomatic. identified across the whole Spanish geography. Although The three HTLV-2 cases were two donors and one many were immigrants from endemic areas, mostly in recipient. All had been born in Spain. The last patient Latin America, up to 18% were native Spaniards [6]. died before transplantation. The two donors were finally The rapid development of subacute myelopathy was discharged from transplantation because they were also seen in one of our recipients from a kidney from the positive for HIV and hepatitis C. HTLV-1 positive cadaveric donor. Similar cases of sub- acute myelopathy shortly after transplantation have already been reported in the literature [12–14], including Discussion a series of recipients from a single donor in Spain [15]. More than 35 years after the discovery of HTLV-1 [7], Myelopathy was originally reported in a heart transplant donor/recipient screening for the virus remains sporadic recipient in France following HTLV-1 acquisition from or non-existent in most countries. In 1993, the American contaminated blood transfusions during the surgery CDC recommended that persons infected with HTLV be [16]. Transplant immunosuppression seems to play a counselled “not to donate blood, semen, body organs or major role in the accelerated disease progression in this other tissues” [8]. Nevertheless, in the year 2009 the rec- setting [17]. ommendation for universal HTLV screening in deceased In response to the worldwide evolving foci of HTLV-1 organ donors was dropped in the United States because of infections and the very poor prognosis of post-transplant the perception of low HTLV-1 prevalence and low positive virus-associated illnesses, there are urgent calls for a predictive value of serologic screening tests [9]. Alongside broader HTLV-1 screening of live and -more difficult- de- this recommendation, most international transplant soci- ceased organ donors. Organ procurement organizations ety guidelines currently do not provide any advice on and transplant programs should determine local preva- HTLV-1 screening and use of donated organs. lence to guide HTLV-1 screening efforts [10]. Targeted High rates of HTLV-1 have been found in specific screening of potential high-risk living (and deceased) do- groups in non-endemic regions of North America [10] nors for HTLV-1 has been recommended by some authors and Europe [11], and decades of migration/immigration [13]. Suggestions also have been put forward for national and tourism/travelling have altered the demographics of or international registries of all HTLV-1-affected trans- many Western countries. For example, the ongoing plants [17]. Alerted to the dangers of rapid-onset TSP refugee migration from the Middle East and Africa following HTLV-1-infected organ transplants, Japan began would rapidly change the prevalence of HTLV-1 in many in 2014 screening for HTLV-1 of all kidney donations. European countries. For a while this has been the case Similarly, the United Kingdom issued new transplantation with Latin Americans in Spain, given the large flux of guidance on HTLV-1 screening of cadaveric solid organs de Mendoza et al. BMC Infectious Diseases (2019) 19:706 Page 4 of 5 in 2011. Finally, the Global Virus Network has recently (Hospital Cristal-Piñor, Orense); E. Poveda (INIBIC-Complejo Hospitalario called for more systematic HTLV-1 screening before solid Universitario, A Coruña); E. Calderón (Hospital Virgen del Rocío & CIBERESP, Sevilla); D. Escudero (Hospital Germans Trias i Pujol, Barcelona); M. Trigo, J. organ transplantation everywhere [4]. Diz & M. García-Campello (Complejo Hospitalario, Pontevedra); M. Rodríguez- The screening costs for HTLV-1 are small in compari- Iglesias (Hospital Universitario, Puerto Real); A. Hernández-Betancor & A.M. son with the cost of post-transplant illnesses and/or Martín (Hospital Insular Hospital Universitario, Las Palmas de Gran Canaria); J.M. Ramos & A. Gimeno (Hospital Universitario, Alicante); F. Gutiérrez, J.C. death associated with TSP or ATL following HTLV-1 Rodríguez & V. Sánchez (Hospital General, Elche); C. Gómez-Hernando infection [18]. For all these reasons, the American and (Complejo Hospitalario Virgen de la Salud, Toledo); G. Cilla & E. Pérez-Trallero European CDCs along with other health prevention (Hospital Donostia, San Sebastián); J. López-Aldeguer (Hospital La Fe, Valencia); L. Fernández-Pereira (Hospital San Pedro de Alcántara, Cáceres); J. agencies should urgently update their policy recommen- Niubó (Ciudad Sanitaria de Bellvitge, Barcelona); M. Hernández, A.M. dations on organ transplant HTLV-1 screening. In the López-Lirola & J.L. Gómez-Sirvent (Hospital Universitario La Laguna, Tenerife); meantime, some transplant centres around the world, L. Force (Hospital General, Mataró); C. Cifuentes (Hospital Son Llátzer, Palma de Mallorca); S. Pérez & L. Morano (Hospital do Meixoeiro, Vigo); C. Raya including a few in Spain, have already implemented (Hospital del Bierzo, Ponferrada); A. González-Praetorius (Hospital “rapid” (or “urgent”) HTLV-1 testing of all deceased Universitario, Guadalajara); J.L. Pérez & M. Peñaranda (Hospital Son Espases, organ donors. In parallel, diagnostic companies should Mallorca); S. Hernáez-Crespo (Hospital de Basurto, Bilbao); J.M. Montejo (Hospital de Cruces, Bilbao); L. Roc & A. Martínez-Sapiña (Hospital Miguel design rapid tools (i.e., point-of-care (PIC) assays) and Servet, Zaragoza); I. Viciana (Hospital Virgen de la Victoria, Málaga); T. improve the specificity of HTLV-1 screening tests to Cabezas, A. Lozano & J.M. Fernández (Hospital de Poniente, Almería); I. minimize unwanted organ discharge. García-Bermejo & G. Gaspar (Hospital Universitario, Getafe); R. García, M. Górgolas, C. Vegas & J. Blas (Fundación Jiménez Díaz, Madrid); P. Miralles, M. Our findings call into question the current view that Valeiro & T. Aldamiz (Hospital Gregorio Marañón, Madrid); N. Margall (Hospital anti-HTLV screening of donated organs is not needed or Santa Creu i Sant Pau, Barcelona); C. Guardia & E. do Pico (ICS, Barcelona); I. just recommended when there is suspicion, as it is Polo, A. Aguinaga & C. Ezpeleta (Complejo Hospitalario Navarra, Pamplona); S. Sauleda & M. Pirón (Banco de Sangre & Tejidos, Barcelona); R. González & recommended in Spain [5]. This opinion is based on the L. Barea (Centro de Transfusiones, Madrid); A. Jiménez & L. Blanco (Centro de assumption that HTLV-1-associated diseases will Hemoterapia y Hemodonación de Castilla y León, Valladolid); A. Suárez & I. develop only in a small proportion of carriers and that Rodríguez-Avial (Hospital Clínico San Carlos, Madrid); A. Pérez-Rivilla, P. Parra & M. Fernández (Hospital Universitario 12 de Octubre, Madrid); M. Fernández- progression to disease is slow compared with the average Alonso (Clínica Universitaria, Pamplona); A. Treviño, S. Requena, L. Benítez-Gu- lifespan of humans and therefore poses no major threats tiérrez, V. Cuervas-Mons & C. de Mendoza (IIS Hospital Universitario Puerta de to public health. In the transplant setting, the very high Hierro, Majadahonda); P. Barreiro (La Paz University Hospital, Madrid); V. Soriano, O. Corral & F. Gómez-Gallego (UNIR Health Sciences School & risk of transmission and the high rate along with short- Medical Centre, Madrid). term for developing HTLV-1 disease most likely results from immunosuppressive therapy. Authors’ contributions CdM, VS, LR, RB and AA designed the study. CdM and VS wrote the draft; CdM, LR, RB, GR, JMR, CG, AA, MRI, JGC and MFA selected patients and Conclusion provided samples tested in the study. CdM and VS did statistical analyses. All We report a low but not negligible rate of HTLV-1 infec- authors revised the draft, completed information and provided comments. All authors read and approved the final manuscript. tion among donors and recipients of solid organ trans- plants in Spain. Of note, unaware HTLV-1-infected Funding donors were not exclusively foreigners from highly none endemic areas but native Spaniards that most likely have Availability of data and materials been exposed to HTLV-1 by sexual contact. Therefore, The Spanish HTLV database is a public registry ascribed to a public universal HTLV screening should be recommended in all institution, Puerta de Hierro University Hospital, located in Madrid. The donor and recipients of solid organ transplantation in person responsible for granting access is Dr. Carmen de Mendoza, first author of this manuscript and current coordinator of the Spanish HTLV Spain. Evidence is overwhelming for very high -if not uni- Network. form- virus transmission and increased risk as well as rapid disease progression, mostly subacute myelopathy. Ethics approval and consent to participate the study was approved by the hospital ethics committee of the reference Abbreviations center, Puerta de Hierro University Hospital. According to the normative in CDC: Center for Diseases Control and Prevention; ELISA: Enzyme-linked place, adherence to it was acknowledged by the Ethics committee of the immune serum assay; HAM HTLV: Associated myelopathy; HTLV-1: Human T remaining participating centres. lymphotropic virus type 1; TSP: Tropical spastic paraparesis Consent for publication Acknowledgements All authors have read and approved the current submission. We would like to thank all members of the HTLV Spanish Network. C. Rodríguez, M. Vera & J. del Romero (Centro Sanitario Sandoval, Madrid); G. Competing interests Marcaida & M.D. Ocete (Hospital General Universitario, Valencia); E. Caballero The authors declare that they have no competing interests. & I. Molina (Hospital Vall d’Hebrón, Barcelona); A. Aguilera, J.J. Rodríguez- Calviño, D. Navarro, C. Rivero & M.D. Vilariño (Hospital Conxo-CHUS, Author details 1 Santiago); R. Benito, S. Algarate & J. Gil (Hospital Clínico Universitario Lozano Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. 2 Blesa, Zaragoza); R. Ortiz de Lejarazu & S. Rojo (Hospital Clínico Universitario, Universidad CEU-San Pablo, Madrid, Spain. 3Hospital Miguel Servet, Valladolid); J.M. Eirós & A. San Miguel (Hospital Rio Hortega, Valladolid); C. Zaragoza, Spain. 4Hospital Lozano Blesa, Zaragoza, Spain. 5Clínica Manzardo & J.M. Miró (Hospital Clínic-IDIBAPS, Barcelona); J. García & I. Paz Universitaria de Navarra, Pamplona, Spain. 6Hospital General Universitario, de Mendoza et al. 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