Human T-lymphotropic virus type 1 (HTLV-1) infection is a neglected disease despite affecting roughly 15 million people worldwide [1,2]. As in HIV infection, chronicity uniformly occurs following acute HTLV-1 infection with no self-limited episodes. However, lifelong less than 10% of HTLV-1 carriers may develop clinical manifestations, including two life-threatening illnesses, namely a subacute invalidating myelopathy known as tropical spastic paraparesis (TSP)  and an acute T-cell leukemia/lymphoma (ATL) . As other human retroviruses, HTLV-1 infects CD4+ T lymphocytes; however, instead of causing cell lysis and immunodeficiency (including AIDS) as HIV-1 and HIV-2, HTLV-1 cause dysfunction and/or immortalization of infected cells. Proliferation of infected CD4+ T cells may progress to ATL, whereas TSP represents a pathological immune response to HTLV-1 antigens within the spinal cord (Fig. 1).
In contrast with HIV-1 and HIV-2, whose epidemic origin jumping from primates to humans has been dated within the last century, HTLV-1 has been infecting humans for thousands of years, as proven in fossil mummies from Latin America . Following acute HTLV-1 infection, the viral genome integrates within CD4+ T lymphocytes and expands mostly through viral synapses and cell proliferation . This explains that plasma viremia is absent in HTLV-1 carriers. A strong cytotoxic T-lymphocyte response by the host is elicited against the virus, establishing within a few weeks a relatively stable proportion of CD4+ infected T cells per study participants (proviral set point), which has clinical prognostic value . The median HTLV-1 proviral load in TSP patients is of 5.4 copies/100 peripheral blood mononuclear cells, whereas asymptomatic carriers have a median of 0.3 copies/100 cells. Interestingly, proviral load in HTLV-1 is much higher than in HIV-1 that generally is found integrated in less than 1/1000 peripheral blood cells. Persons with HLA A*02 or C*08 exhibit high immune responses to the HBZ protein of HTLV-1, reducing the proviral load and ultimately the risk of HTLV-1 associated diseases . In contrast with HIV, HTLV-1 exhibits low genetic variability as viral expansion occurs through cell proliferation and rarely involves the reverse transcriptase viral enzyme. Integration of proviruses at distinct host chromosome sites is followed by oligoclonal proliferation. A wide number of clones can be recognized, ranging from 104 to 105 clones per patient . Contact of integration proviruses nearby certain host gene (insertional mutagenesis) may ultimately led to leukemogenesis [10,11].
HTLV-1 is efficiently transmitted perinatally (breastfeeding), sexually (more from men to women), and parenterally (transfusions, IDU. and transplants) . The diagnosis is based on the demonstration of specific serum HTLV-1 antibodies. A high HTLV-1 proviral load predicts both the risk of disease development  and of sexual transmission . To date there is neither prophylactic vaccine nor effective antiviral therapy .
There are highly endemic regions for HTLV-1 infection in South Japan, Iran, Papua New Guinea, Sub-Saharan Africa, parts of South America, and the Caribbean basin [1,2]. HTLV-1 infection is rather rare among native Europeans but in Romania . However, the rate of HTLV-1 infection in Europe has been on the rise during the last decades, largely among immigrants from endemic areas, travellers and their sexual contacts [14,15].
The Spanish human T-lymphotropic virus type 1 registry
A national registry of HTLV-1 cases exists in Spain since 1988, when the first individuals with HTLV-1 infection were reported . A total of 327 cases of HTLV-1 infection had been diagnosed until December 2016. Overall, 62% were immigrants from Latin America and 13% came from Africa, being only 19% native Spaniards. Men were 39% and median age at diagnosis was 41*years old. Table 1 summarizes the main features of the HTLV-1 population reported to date at the Spanish registry.
HTLV-1 cases in Spain are concentrated around the largest urban areas (Madrid and Barcelona) where the greatest immigrant populations are living. However, HTLV-1-infected persons have been identified across the whole Spanish geography (Fig. 2). Of the nearly 47 million people currently living in Spain, around 4.5 million are foreigners. In addition, 75 million visitors/tourists came to Spain during year 2016, more than 10% from HTLV-1 endemic regions. Figure 3 records the country of origin of foreigners with HTLV-1 infection reported in Spain.
Symptomatic HTLV-1 infections have been diagnosed in 58 (18%) of viral carriers living in Spain, being TSP in 33 and ATL in 25 patients. New diagnoses of HTLV-1 infection have risen sharply in Spain since 2008 (Fig. 4), largely as result of introducing HTLV screening in blood banks and the continuous growing arrival of immigrants and tourists from endemic regions . However, the current incidence of newly HTLV-1 diagnoses in Spain remains stable, around 20–25 cases yearly.
In year 2016, a total of 21 new cases of HTLV-1 were diagnosed in Spain. Only two were native Spaniards, being 16 Latin Americans, two Africans, and one from Romania. Four (19%) presented with symptomatic disease, including three with ATL and one with TSP. Twelve asymptomatic carriers were newly diagnosed in blood banks as first-time donors.
Transplantation and human T-lymphotropic virus type 1 transmission and disease
Spain is the world leading country performing solid organ transplants. The annual figure is steadily rising, being currently of nearly 5000 transplants/year. To date, more than 100 000 individuals have benefit from organ donations. More than 60% are kidney transplants, with liver being the second most frequent allograft. Heart, lung, and pancreas are transplanted less frequently.
Rapid-onset subacute myelopathy and T lymphomas associated with HTLV-1 infection have both been reported following solid organ transplantation. At least three different scenarios have been described for HTLV-1 acquisition and disease in the transplantation setting, including infection from the organ donor, contaminated blood transfusions during surgery, and baseline carriage of HTLV-1 by the recipient [18,19]. It seems that the immunosuppression used to avoid organ rejection (e.g. corticoids, tacrolimus, cyclosporine, mycophenolate and so on) plays a major role in rapid-onset disease development in this population [18,19].
Cases of TSP shortly after transplantation have been reported in Japan, as well as in North America and Europe, despite the low rate of HTLV-1 infection in the latest regions (Table 2) [20–29]. Myelopathy was originally reported in a heart transplant recipient in France following HTLV-1 acquisition from contaminated blood transfusions during the surgery . In Spain, two kidney and one liver transplant recipients that received organs from a single deceased HTLV-1 donor developed TSP within 2 years . More recently, in the United States two kidney transplant recipients from separate infected donors developed TSP [26,27].
During year 2016, one kidney transplant recipient in Spain developed TSP within the first year of surgery. Interestingly, a second kidney transplant recipient from the same infected donor, a native Spaniard, became also infected with HTLV-1 but to date has not developed any disease . However, this second allograft was removed after rejection 6 months following transplantation and since then the patient has no longer being under immunosuppressants.
In Japan, where HTLV-1 is quite prevalent, cases of TSP have been reported following either kidney or liver transplants [21,22,24,29–31]. More interesting, however, is the diagnosis of ATL shortly following solid organ transplants, mostly among native Japanese recipients already infected with HTLV-1 [31–33]. Similar cases have been reported in other places [34,35]. This is somewhat unique as most posttransplant lymphoproliferative disorders are of B lymphocytes and linked to Epstein-Barr virus infection. Anecdotally, in Germany, transplanted kidneys and a liver resulted in primary cutaneous T-cell lymphoma in at least two patients infected from a single HTLV-1 donor . Table 3 summarizes the major features of ATL cases reported so far following solid organ transplantation.
These findings call into question the current view that anti-HTLV screening of donated organs is unnecessary. This opinion is based on the assumption that HTLV-1-associated diseases will develop only in a small proportion of carriers and that progression to disease is slow compared with the average lifespan of humans and, therefore, poses no major threats to public health . We hypothesize that the very high risk for short-term development of HTLV-1 is the result of immunosuppressive therapy. However, generally there is a divergent predominant clinical manifestation depending on whether the allograft derives from an HTLV-1-infected donor or it is the recipient who actually carries the virus (Fig. 5).
More than 35 years after the discovery of HTLV-1 , donor/recipient screening for the virus remains sporadic or nonexistent in most countries . In 1993, the American Centers for Disease Control (CDC) recommended that persons infected with HTLV be counselled ‘not to donate blood, semen, body organs or other tissues ’. Nevertheless, in the year 2009 the recommendation for universal HTLV screening in deceased organ donors was dropped in the United States because of the perception of low HTLV-1 prevalence, low positive predictive value of serologic screening tests, and a lack of procedures appropriate for use by organ procurement agencies . Moreover, most international transplant society guidelines currently do not provide recommendations on HTLV-1 screening and use of donated organs .
High rates of HTLV-1 have been found in specific groups in nonendemic regions of North America [41,42] and Europe , and decades of migration/immigration and tourism/travelling have altered the makeup of many Western countries. In particular, the ongoing refugee migration from the Middle East and Africa is likely to significantly alter the prevalence of HTLV-1 in many European countries . In Spain, this has been the case with Latin Americans for a while, given the large flux of immigration facilitated by strong cultural and ancestor links . In response to these evolving foci of HTLV-1 infections and the very poor prognosis of posttransplant TSP and ATL, there are urgent calls for a broader HTLV-1 screening of live and more difficult deceased organ donors.
Organ procurement organizations and transplant programs should determine local prevalence to guide HTLV-1 screening efforts . Targeted screening of potential high-risk living (and deceased) donors for HTLV-1 has been recommended by some experts [26,44] Suggestions also have been put forward for national or international registries of all HTLV-1-affected transplants . Alerted to the dangers of rapid-onset TSP following HTLV-1-infected organ transplants, Japan begun in 2014 screening for HTLV-1 of all kidney donations. Similarly, the United Kingdom issued new transplantation guidance on HTLV-1 screening of cadaveric solid organs in 2011. Finally, the Global Virus Network has recently called for more systematic HTLV-1 screening before solid organ transplantation everywhere .
It has been highlighted that ‘whereas not screening donors… for HIV infection would be considered unethical, the same is not the case for HTLV-1, another human retrovirus, where risk assessments are made based on the predicted prevalence of cases among donors, the probable risk of transmission, and the subsequent likelihood of disease .’ Yet, those risks estimates are based on inadequate national epidemiology, ignoring changing demographics in many countries , and a poor understanding of the transplant-acquired HTLV-1 disease risk [18,19]. The screening costs for HTLV-1 are small in comparison with the cost of posttransplant illness and/or death associated with TSP or ATL following HTLV-1 infection . For all these reasons, the American and European CDCs along with other health prevention agencies should urgently update their policy recommendations on organ transplant HTLV-1 screening. In the meantime, some transplant centres around the world, including a few in Spain, have already implemented ‘rapid’ (or ‘urgent’) HTLV-1 testing of all living and deceased organ donors.
Human T-lymphotropic virus type 1 in pregnancy
Vertical transmission is one of the major mechanisms of HTLV-1 contagion in endemic regions, and mainly occurs through prolonged breastfeeding [45–47]. Without intervention, roughly 20% of newborns from HTLV-1-positive mothers become infected . Accordingly, HTLV antenatal screening is recommended in most endemic regions and HTLV-infected mothers are advised to bottle feed their infants [46,47]. In Europe, HTLV screening in antenatal clinics is not mandatory in most countries. However, the large flux of immigrants from HTLV endemic areas, many of them women of childbearing age, has compelled a reappraisal of this policy .
In a multicentre survey conducted in 2010, we tested for HTLV antibodies in a large number of foreign pregnant women living in Spain . The prevalence of HTLV infection in this population was 0.2%, which was more than 40-fold higher than the rate reported in a study conducted 5 years earlier, in which only one HTLV-2 infection was found during testing of almost 20 000 native pregnant women . In contrast, six out of the seven HTLV-positive foreign pregnant women in the 2010 study had HTLV-1 and came from endemic regions in Latin America. Our results were in agreement with data from other European countries, such as the United Kingdom and France, where the prevalence of HTLV infection among native pregnant women was very low, but significantly higher among those coming from HTLV-1 endemic regions (0.5 and 0.9%, respectively) [52,53].
Recognition of HTLV-1 in native European pregnant women is on the rise given that persons from endemic regions are often their sex partners, and HTLV-1 is efficiently transmitted by sex, especially from men to women [2,12]. One of the 21 cases of HTLV-1 reported in Spain during year 2016 was a native Spaniard pregnant woman. Unfortunately, information on her current or past sex partners was not available. Based on these considerations, it was believed in the past that targeting only high-risk pregnant women populations could be more cost-effective than universal antenatal testing. However, the benefit of avoiding vertical HTLV-1 transmission should be stressed. Identification of HTLV-1 in any pregnant woman, either native or foreigner, would allow periodic individual monitoring and potentially early disease recognition, prevent further sexual transmissions, and avoid newborn infections. Antenatal screening for HIV is mandatory in Spain with rates ranging from 0.1% in native Spaniards to 0.26% among foreign pregnant women .
Owing to inadequate treatment options for TSP or ATL and the lack of vaccine, prevention of new HTLV-1 infections can only be made by halting transmission chains either parenterally, sexually or from mother-to-child. Of the latest two, interventions on sex behaviours may be more difficult than advising on avoiding breastfeeding in HTLV-seropositive mothers. In particular circumstances, as in developing regions where poor socioeconomic conditions and/or serious risk of gastrointestinal infections of newborns make breastfeeding unavoidable, short-term breastfeeding for a maximum of up to 6 months could be an alternative option .
Children born in the past from mothers recently known to be HTLV-1 carriers should be screened for HTLV and those found to be positive must be monitored periodically, as they represent a subset of individuals with a greater risk for developing ATL besides TSP. Similarly, spouses, brothers/sisters, parents and close relative family members should be tested at least once shortly after new HTLV-1 persons are identified.
Human T-lymphotropic virus type 1 and blood banks
More than 1 700 000 blood donations (∼37/1000 habitants) are performed in Spain annually. Blood banks in Spain slowly began anti-HTLV-1 screening in the year 2008, being currently made at the largest blood centres across the country. However, no mandatory official order for HTLV testing of blood donors has been made so far in Spain. In contrast, HTLV screening of organ and tissue donors in Spain was released in 2012, which was revised in 2014 (Boletin Oficial Estado, 5 November, pp. 90536–90538) dictating that ‘HTLV screening should be made in donors that came or lived in highly endemic regions, or have either sex partners or parents from those regions’.
For seroepidemiological surveys, testing pools adequately has been shown to preserve enough sensitivity while it may drastically reduce false positives . This is an important issue, as high false-positive rates testing low-risk HTLV-1 populations as blood donors is relatively common using most commercial enzyme immunoassays . This circumstance has hampered a more rapid and broader implementation of HTLV-1 screening policies, because of concerns on unnecessary discharge of blood products [37,57].
During the last decade, blood banks have contributed annually with more than half of new HTLV-1 diagnoses in Spain (Fig. 4). Indeed, 12 out of 21 new cases reported during the year 2016 were identified in first-time blood donors. Even so, the current estimated HTLV-1 seroprevalence is below 1/100 000 donations in Spain, similar to that reported in other Western countries [58–60].
The introduction of leukoreduction procedures more than a decade ago in blood banks has drastically minimized the risk of HTLV transmission [61,62]; however, universal HTLV screening of first donors may still be a cost-effective strategy. Beyond the individual benefit of unmasking the HTLV-1 carrier status, that makes possible periodic medical monitoring and potential earlier disease diagnoses, there is a public health value. Unveiling HTLV-1 carriers would provide an opportunity to prevent further transmission by sex or breastfeeding, as well as identification of relatives unaware of their infection.
In Europe and Japan, most HTLV-positive donors are HTLV-1, whereas in the United States HTLV-2 is more frequently reported in blood banks . Anyway, recent estimates of HTLV infection in blood donations in Western countries have shown very low rates, indeed below five per million in France and the United States [60,64]. In this context, it seems reasonable to limit anti-HTLV screening to first-time donors. Decisions to stop HTLV screening of donors, as it has recently been made in Finland and Norway, seems not justified, and especially considering the large influx of immigrants from HTLV-1 endemic areas currently going to Northern Europe.
Human T-lymphotropic virus type 1 coinfections: sexually transmitted infections and hepatitis C
HTLV-1 is efficiently transmitted by sex [2,6]. Thus, it seems reasonable to suspect that persons with sexually transmitted infections could represent a target high-risk group for unveiling HTLV-1 infections. Similarly, HTLV-1 is a blood-borne pathogen and there is currently a large effort for screening and curing persons infected with the hepatitis C virus (HCV), another parenterally transmitted agent. Can we use individuals with sexually transmitted infections or chronic hepatitis C as target screening populations for unmasking HTLV-1 infections?
Information on HTLV-1 seroprevalence is scarce for persons with sexually transmitted infections, although the virus is transmitted sexually and there are a large number of immigrants from endemic regions. In a study we conducted 15 years ago in Madrid, the rate of HTLV-1 infection was low in foreign commercial sex workers. Despite being mostly Africans and Latin Americans, only two persons were found testing 762. As reference, 5.2% were positive for HIV-1, 3.5% for hepatitis B surface antigen, and 3% for syphilis antibodies . We concluded that HTLV testing of persons presenting with sexually transmitted infections in Spain would not contribute much to unmask HTLV-1 carriers.
The interest for examining HTLV and HCV overlapping epidemics is double. HCV populations could be an enriched group for HTLV-1 on one hand, and liver disease could be different in HCV–HTLV coinfected individuals. Roughly 80 million people worldwide are estimated to suffer from chronic hepatitis C . In contrast with HTLV-1 or HIV, around 25% of individuals with acute hepatitis C clears the virus spontaneously within 6 months . The remaining 75% goes to develop chronic hepatitis C and become at risk for developing liver cirrhosis and occasionally hepatocellular carcinoma . In most Western countries, chronic HCV infection is the major cause for liver transplantation . As HTLV-1, HCV is a blood-borne pathogen, and not surprisingly is often diagnosed in persons coinfected with other viruses sharing the same transmission routes. However, in contrast with retroviruses, HCV transmission by sex is rare , although recent outbreaks of acute hepatitis C among homosexual men have changed this view .
The natural history of chronic hepatitis C is well known to be accelerated in patients coinfected with HIV and/or HBV, largely because of persistent immune activation and chronic inflammation . In contrast, there is limited information on the rate of HCV and HTLV coinfection, and particularly on the influence of HTLV on HCV-related liver disease progression and/or treatment outcomes [71,72].
Several studies, mostly from Japan and Brazil, have suggested that HTLV coinfection may enhance HCV replication and viral load, leading to lower HCV responses to interferon in the past, and accelerated HCV liver disease progression [71–76]. Data from Japan even have suggested that HTLV could enhance the risk of developing liver cancer in HCV carriers [73,74]. On the other hand, no data exist on the potential influence of HCV on HTLV pathogenicity. Hypothetically, immune activation and chronic inflammation driven by persistent replication of one virus may provide a continuous stimulus for replication of other coexisting viruses, as already being demonstrated in the HIV setting . In this regard, however, a recent report could not link HCV coinfection with increased risk of HTLV-1 sexual transmission .
In Spain, HTLV underdiagnosis is highlighted by the high proportion of first diagnosis presenting either with TSP or ATL [15,77]. The recent recommendation for expanding HCV screening in North America and Europe, to unveil the large number of people unaware of their hepatitis C that could benefit from new antiviral therapies, might provide a unique opportunity for identifying a sentinel group in which HTLV testing might be cost-effective.
The seroprevalence of HTLV was recently examined in 3838 HCV-seropositive individuals in Spain . The overall prevalence of HTLV infection in HCV-seropositive persons was 1.3%, more than 10-fold higher than in the general population attending Spanish outclinics . However, HTLV-1 was only found among foreigners coming from endemic countries in Latin America, whereas HTLV-2 was mostly found in native Spaniards with history of prior IDU and HIV coinfection. Therefore, we concluded that HTLV testing of newly diagnosed HCV individuals would not contribute much to improve late HTLV-1 diagnosis.
A need for unveiling human T-lymphotropic virus type 1 carriers in Spain
Underdiagnosis of HTLV-1 infection in Spain is estimated to be elevated, given the high proportion of new diagnosis presenting with either TSP or ATL . Based on distinct serosurveys, we estimate that roughly 10 000 HTLV-1 infected persons are living in Spain. Briefly, this figure was inferred taking into account HTLV-1 rates that have been found testing distinct risk populations (pregnant women, blood donors, transplant donors and recipients, HIV positives, persons with STDs, leukemic, and neurological patients and so on) [16,17,50,51,54,65,77–79] and the amount of people estimated for each category at national level .
Many countries currently perform antibody screening for HTLV-1 infection in blood donors, and this intervention is likely cost-effective in preventing HTLV-1 related diseases in high prevalence countries. However, a number of high-income countries with low prevalence of HTLV-1 infection also perform universal HTLV-1 screening and debate has arisen regarding its cost-effectiveness in blood banks. Filter-based leukoreduction substantially reduces HTLV-1 transmission by removing infected lymphocytes [61,62]. However, universal HTLV screening of first-time donors perhaps – using pools – would contribute to unveil the relatively high proportion of individuals and their relatives unaware of their HTLV status. Their identification would facilitate medical surveillance and earlier disease diagnosis as well as prevent further transmissions to sex partners and/or newborns.
Given that HCV and HTLV-1 share transmission routes, we hypothesize that dual infection could be particularly frequent. To answer this question we examined whether the renewed efforts for expanding HCV testing for antiviral curative purposes could provide a unique sentinel population that might selectively be targeted to unveil asymptomatic HTLV-1 carriers. The overall prevalence of HTLV infection was 1.3%, more than 10-fold greater than in the general Spanish outpatient population . However, immigrants from HTLV-1 endemic regions and former IDU with HTLV-2 infection were the major contributory risk groups in HCV patients. Therefore, our results suggested that HTLV testing of newly diagnosed HCV individuals would not contribute much to improve late HTLV-1 diagnosis.
At this time, HTLV screening of first-time donors in blood banks, pregnant women and donor-recipient transplants seem to be the most cost-effective strategies to identify asymptomatic HTLV-1 carriers in Spain (Table 4). People coming from HTLV-1 endemic regions, their sexual contacts or children are overrepresented among newly diagnosed HTLV-1 individuals in any of these groups. As HTLV-1-infected mothers may largely prevent transmission to their newborns avoiding breastfeeding and TSP may develop more frequently and rapidly in transplant recipients, it seems worthwhile to recommend universal HTLV screening in at least these two populations in Spain, where immigrants from endemic regions, mostly Latin America, are largely represented.
HTLV-1 infection is a neglected disease despite infecting 15 million people worldwide. Although Spain is not an endemic region, to date 327 HTLV-1 carriers have been notified, of whom 59 have suffered a life-threatening disease. Persons coming from HTLV-1 endemic regions, mostly in Latin America, their sexual contacts or their children are overrepresented in the Spanish HTLV-1 register.
As HTLV-1-infected mothers may prevent transmission to their newborns avoiding breastfeeding and severe HTLV-1 diseases may develop more frequently and rapidly in transplant recipients, universal HTLV screening of these two populations should be mandatory in Spain, and similarly in other nonendemic countries with similar influxes of immigrants from endemic regions.
C.M. and V.S. designed the study and wrote the manuscript. A.T. and S.R. have been in charge of the database for the national network. All other authors significantly contributed providing information on HTLV positive cases. All authors have seen and approved the current submission.
Spanish HTLV Network: C.R., M. Vera, and J. del Romero (Centro Sanitario Sandoval, Madrid); G. Marcaida and M.D. Ocete (Hospital General Universitario, Valencia); E.C. and I. Molina (Hospital Vall d’Hebró, Barcelona); A.A., J.J. Rodríguez-Calviño, D. Navarro, C.R., M.D. Vilariño (Hospital Conxo-CHUS, Santiago); R.B., S. Algarate & J. Gil (Hospital Clínico Universitario Lozano Blesa, Zaragoza); R.O.L. and S.R. (Hospital Clínico Universitario, Valladolid); J.M.E. and A. San Miguel (Hospital Rio Hortega, Valladolid); C.M. and J.M. Miró (Hospital Clínic-IDIBAPS, Barcelona); J.G.C. and I. Paz (Hospital Cristal-Piñor, Orense); E. Poveda (INIBIC-Complejo Hospitalario Universitario, A Coruña; E.C. (Hospital Virgen del Rocío & CIBERESP, Sevilla); D. Escudero (Hospital Germans Trias i Pujol, Barcelona); M. Trigo, J. Diz and M. García-Campello (Complejo Hospitalario, Pontevedra); M. Rodríguez-Iglesias (Hospital Universitario, Puerto Real); A. Hernández-Betancor and A.M. Martín (Hospital Insular Hospital Universitario, Las Palmas de Gran Canaria); J.M.R. and A. Gimeno (Hospital Universitario, Alicante); F. Gutiérrez, J.C. Rodríguez and V. Sánchez (Hospital General, Elche); C. Gómez-Hernando (Complejo Hospitalario Virgen de la Salud, Toledo); G. Cilla and E. Pérez-Trallero (Hospital Donostia, San Sebastián); J. López-Aldeguer (Hospital La Fe, Valencia); L. Fernández-Pereira (Hospital San Pedro de Alcántara, Cáceres); J. Niubó (Ciudad Sanitaria de Bellvitge, Barcelona); M. Hernández, A.M. López-Lirola, and J.L. Gómez-Sirvent (Hospital Universitario La Laguna, Tenerife); L. Force (Hospital General, Mataró); C. Cifuentes (Hospital Son Llátzer, Palma de Mallorca); S. Pérez and L. Morano (Hospital do Meixoeiro, Vigo); C. Raya (Hospital del Bierzo, Ponferrada); A. González-Praetorius (Hospital Universitario, Guadalajara); J.L. Pérez and M. Peñaranda (Hospital Son Espases, Mallorca); S. Hernáez-Crespo (Hospital de Basurto, Bilbao); J.M. Montejo (Hospital de Cruces, Bilbao); L. Roc and A. Martínez-Sapiña (Hospital Miguel Servet, Zaragoza); I. Viciana (Hospital Virgen de la Victoria, Málaga); T. Cabezas, A. Lozano and J.M. Fernández (Hospital de Poniente, Almería); I. García-Bermejo and G. Gaspar (Hospital Universitario, Getafe); R. García, M. Górgolas, C. Vegas and J. Blas (Fundación Jiménez Díaz, Madrid); P. Miralles, M Valeiro, and T. Aldamiz (Hospital Gregorio Marañón, Madrid); N. Margall (Hospital Santa Creu i Sant Pau, Barcelona); C. Guardia and E. do Pico (ICS, Barcelona); I. Polo, A. Aguinaga and C. Ezpeleta (Complejo Hospitalario Navarra, Pamplona); S. Sauleda and M. Pirón (Banco de Sangre & Tejidos, Barcelona); P. Torres, R. González (Centro de Transfusiones, Madrid); A. Jiménez and L. Blanco (Centro de Hemoterapia y Hemodonación de Castilla y León, Valladolid); A. Suárez and I. Rodríguez-Avial (Hospital Clínico San Carlos, Madrid); A. Pérez-Rivilla, P. Parra, and M. Fernández (Hospital Universitario 12 de Octubre, Madrid); M. Fernández-Alonso (Clínica Universitaria, Pamplona); A. Treviño, S. Requena, I. Carrasco, M. Cuesta, L. Benítez-Gutiérrez, V. Cuervas-Mons, and C. de Mendoza (IIS Hospital Universitario Puerta de Hierro, Majadahonda); P. Barreiro and V. Soriano (Hospital Universitario La Paz, Madrid).
The work was funded in part by grants from F-IES and ISCIII-Fondos Feder (PI13/01574; ICI14/00372; CD14/0243; FI14/0264; CM13/0309; CES12/003).
Conflicts of interest
There are no conflicts of interest.
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