International Journal of Infectious Diseases 122 (2022) 970–975 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid Late presentation of human T-lymphotropic virus type 1 infection in Spain reflects suboptimal testing strategies Carmen de Mendoza 1,∗∗, Leire Pérez 2, Mario Fernández-Ruiz 3, María José Pena 4, José Manuel Ramos 5, Alberto Richart 6, María Piron 7, Ariadna Rando 8, Elisenda Miró 9, Gabriel Reina 10, Beatriz Encinas 1, Silvia Rojo 11, Antonio Manuel Rodriguez-Iglesias 12, Rafael Benito 13, Antonio Aguilera 14, Ana Treviño 15, Octavio Corral 15, Vicente Soriano 15,∗ 1 Internal Medicine Laboratory, Puerta de Hierro University Hospital & Research Foundation-IDIPHISA, Madrid, Spain 2 Internal Medicine Department, Gregorio Marañón University Hospital, Madrid, Spain 3 Infectious Diseases Unit, 12 Octubre University Hospital, Madrid, Spain 4 Microbiology Department, Doctor Negrín University Hospital, Las Palmas de Gran Canaria, Spain 5 Infectious Diseases Unit, Alicante General University Hospital, Alicante, Spain 6 Regional Transfusion Center, Madrid, Spain 7 Catalan Tissue & Blood Bank, Barcelona, Spain 8 Microbiology Department, Vall d’Hebron University Hospital, Barcelona, Spain 9 Microbiology Department, Santa Creu i Sant Pau University Hospital, Barcelona, Spain 10 Microbiology Department, Clínica Universidad de Navarra, Pamplona, Spain 11 Microbiology Department, Hospital Clínico Universitario, Valladolid, Spain 12 Microbiology Department, University of Cadiz, Cadiz, Spain 13 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain 14 Microbiology Department, University of Santiago, Santiago de Compostela, Spain 15 UNIR Health Sciences School & Medical Center, Madrid, Spain a r t i c l e i n f o a b s t r a c t Article history: Objectives: Although only 10% of persons infected with human T-lymphotropic virus type 1 (HTLV-1) Received 4 May 2022 may develop virus-associated illnesses over their lifetime, missing the earlier diagnosis of asymptomatic Revised 10 June 2022 carriers frequently leads to late presentation. Accepted 18 July 2022 Methods: A nationwide HTLV-1 register was created in Spain in 1989. We examined the main demo- graphics and clinical features at the time of the first diagnosis for more than three decades. Keywords: Results: A total of 428 individuals infected with HTLV-1 had been reported in Spain until the end of HTLV-1 2021. Up to 96 (22%) individuals presented clinically with HTLV-1-associated conditions, including sub- Myelopathy acute myelopathy (57%), T-cell lymphoma (34%), or Strongyloides stercoralis infestation (8%). Since 2008, Diagnosis HTLV-1 diagnosis has been made at blood banks (44%) or clinics (56%). Native Spaniards and Sub-Saharan Late presentation Africans are overrepresented among patients presenting with HTLV-1-associated illnesses suggesting that Sexually transmitted infections poor epidemiological and/or clinical suspicion, which led to the late presentation are more frequent in them than carriers from Latin America (LATAM) (31.7% vs 20.4%, respectively; P = 0.015). Conclusion: HTLV-1 infection in Spain is frequently diagnosed in patients presenting with characteris- tic illnesses. Although screening in blood banks mostly identifies asymptomatic carriers from LATAM, a disproportionately high number of Spaniards and Africans are diagnosed too late at the time of clinical manifestations. Expanding testing to all pregnant women and clinics for sexually transmitted infections could help to unveil HTLV-1 asymptomatic carriers. © 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) ∗ Corresponding author: Dr. Vicente Soriano, UNIR Health Sciences School and Medical Center, C/ García Martín 21, Pozuelo de Alarcón 28224, Madrid, Spain ∗∗ Dr. Carmen de Mendoza, Puerta de Hierro University Hospital, C/ Joaquín Ro- E-mail addresses: cmendoza.cdm@gmail.com (C. de Mendoza), vicente.soriano drigo 2 Majadahonda 28222, Madrid, Spain @unir.net (V. Soriano). https://doi.org/10.1016/j.ijid.2022.07.043 1201-9712/© 2022 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) C. de Mendoza, L. Pérez, M. Fernández-Ruiz et al. International Journal of Infectious Diseases 122 (2022) 970–975 Introduction considered positive, indeterminate, or negative for HTLV-1 antibod- ies based on the reactivity to p19, p24, glycoprotein (gp)46, and Human T-lymphotropic virus type 1 (HTLV-1) was the first gp21 (Taylor et al., 1996). described human retrovirus (Poiesz et al., 1980). Viral trans- In samples with HTLV indeterminate results, additional con- mission may occur after sexual, vertical, or parenteral expo- firmation is made using in-house polymerase chain reaction as- sure (Nunes et al., 2017). The virus establishes chronic infec- says with primers, probes, and conditions described elsewhere tion by integrating the viral genome as proviral DNA within (Treviño et al., 2014). Finally, in individuals definitively positive CD4+ T lymphocytes, the main target cells (Bangham, 2018). Over for HTLV-1, quantitative molecular methods are used to provide their lifetime, only 10% of HTLV-1-infected persons may develop estimates of HTLV-1 proviral load, which has prognostic value virus-associated illnesses (Hirons et al., 2021), including HTLV-1- (Furtado et al., 2012). associated myelopathy (HAM) and adult T-cell leukemia/lymphoma All individuals diagnosed with HTLV-1 are referred to clin- (ATLL). Most HTLV-1 carriers remain asymptomatic for decades and ics with infectious diseases specialists for further assessment and may die unaware of their infection. In this way, the transmission follow-up. HTLV-1 carriers are seen once or twice a year, with ap- may occur unknowingly (Legrand et al., 2022). pointments including laboratory checking and clinical assessment, The number of persons infected with HTLV-1 worldwide is not similar to patients with other chronic viral infections (i.e., HIV, well established (Hlela et al., 2009), although recent studies esti- Hepatitis B, etc.). In the subset of patients with HTLV-1-associated mate 10 million people (Gessain and Cassar, 2012; Hirons et al., clinical manifestations, either neurological or hematologic, clini- 2021; Legrand et al., 2022). Hot spots of high endemicity exist cal appointments are more frequent and vary depending on ther- in parts of Japan, Iran, Australia, Melanesia, the Caribbean basin, apeutic interventions adopted. The diagnostic criteria used for ei- South America, and Sub-Saharan Africa (Gessain and Cassar, 2012; ther HAM or ATLL are those recommended by international groups Legrand et al., 2022). The two countries with the largest number of (Bangham et al., 2015; Cook et al., 2019). HTLV-1 carriers are Japan and Brazil (Ito et al., 2021; Rosadas et al., The Spanish HTLV Network annually updates the national fig- 2021). ures for this viral infection and produces recommendations for The growing flow of migrant populations worldwide has screening and/or medical management. geographically expanded the virus across nonendemic regions In this study, we examined the main demographics and clinical (Gessain and Cassar, 2012; Legrand et al., 2022). In Western Eu- features at the time of the first diagnosis in all individuals recorded rope, almost all countries have reported individuals with HTLV- at the HTLV-1 Spanish register up to December 2021. 1 infection. In the United Kingdom and France, many carriers are persons born in the former Caribbean and African colonies Statistical analysis (Couroucé et al., 1993; Ireland et al., 2017). In Spain, the large migrant population from Latin America (LATAM) has contributed Figures are given in absolute numbers and percentages. Quanti- to nearly two-thirds of all HTLV-1 infections recorded to date tative and qualitative variables are described as medians with in- (de Mendoza et al., 2017; Ramos et al., 2020a,2020b). terquartile ranges, mean with SDs, or proportions. Bivariate com- In the absence of epidemiological and/or clinical suspicion, the parisons of quantitative variables were performed using the chi- diagnosis of HTLV-1 is frequently missed or delayed. The lack of square test. recognition of asymptomatic carriers frequently leads to late diag- All statistical analyses were performed using the IBM SPSS noses, with patients presenting after developing clinical manifes- package for Windows version 25.0 (IBM Corp, Armonk, New York). tations and/or having transmitted the virus to sexual partners. De- All tests were 2-tailed, and only P-values <0.05 were considered spite the lack of good treatments for HTLV-1-associated illnesses, significant. either subacute myelopathy or lymphoproliferative diseases, the early recognition of these conditions might significantly improve Results their prognosis (Araujo et al., 2021; Cook et al., 2019). A total of 428 individuals infected with HTLV-1 had been re- Methods ported in Spain until the end of 2021. The study period covers 32 years. The annual incidence of HTLV-1 has remained relatively A nationwide HTLV-1 register was created in Spain in 1989. The stable during the last decade, with roughly 20-25 new diagnoses main demographics, clinical symptoms/signs, and laboratory find- yearly (Figure 1). However, since 2008, the number of HTLV-1 di- ings are collected at baseline and longitudinally using a standard- agnoses has significantly increased because of the introduction of ized case report form. anti-HTLV screening in blood banks. Overall, 302 (73%) HTLV-1 Notification of HTLV-1 cases to the national register is volun- cases recorded in the Spanish registry have been diagnosed over tary. Members of the Spanish HTLV Network cover most lab facil- the last 15 years. ities where HTLV-1 can be diagnosed. In addition, from the coor- Although the largest Spanish cities (i.e., Madrid and Barcelona) dination team, other clinics are contacted when HTLV-1 diagnoses tend to accumulate the greater number of HTLV-1 reported cases, are identified in the National Hospital Discharge database and not there is a wide distribution across the country (Figure 2). In con- previously reported at the register. Further details have been spec- trast, although the country of birth of most foreigners with HTLV- ified elsewhere (Ramos et al., 2020a,2020b). 1 infection is considered endemic, a significant proportion of mi- The diagnostic algorithm for HTLV-1 begins with a screening as- grants with HTLV-1 infection came from neighboring countries that say, with subsequent confirmation of initially reactive samples. The are not considered endemic (Figure 3). screening method used is a commercially available enzyme im- Overall, women represent 62% of all cases. The mean age at di- munoassay (EIA), nowadays marketed by Abbott as it is the most agnosis of HTLV-1 was 42 years old (range 3-78). Migrants from frequently used one (Cassar and Gessain, 2017). Initial EIA-reactive LATAM represent 65%, whereas 17% are native Spaniards, many of sera or plasma is then confirmed with a Western blot or a line im- whom acknowledged having had sex partners from LATAM. Of 22 munoassay (INNO-LIA, Fujirebio). Next, distinct recombinant HTLV- new diagnoses of HTLV-1 reported in Spain during 2021, 2 of 13 1 proteins (p) are absorbed within a strip and then incubated with women were pregnant. clinical specimens. Following recommendations from the HTLV Eu- Up to 96 (22%) individuals first presented clinically with HTLV- ropean Research Network, Western blot or INNO-LIA strips are then 1-associated conditions, including subacute myelopathy (n = 55; 971 C. de Mendoza, L. Pérez, M. Fernández-Ruiz et al. International Journal of Infectious Diseases 122 (2022) 970–975 35 33 30 29 28 25 24 24 23 23 23 22 22 20 20 19 17 17 15 12 12 10 10 9 7 7 7 7 6 5 5 4 4 3 2 2 1 1 1 1 1 1 1 0 Figure 1. Yearly reported cases of HTLV-1 infection in Spain over three decades. HTLV-1; Human T-lymphotropic Virus-1 Figure 2. Geographic distribution of HTLV-1 cases reported in Spain. HTLV-1; Human T-lymphotropic Virus-1 972 C. de Mendoza, L. Pérez, M. Fernández-Ruiz et al. International Journal of Infectious Diseases 122 (2022) 970–975 Figure 3. Country of birth of individuals with HTLV-1 diagnosis in Spain. In bold countries considered as endemic. HTLV-1; Human T-lymphotropic Virus-1 Table 1 Clinical presentationof individuals with HTLV-1 diagnosis in Spain. Total (n=428) LATAM (n=280) SSA (n=49) NS (n=71) LATAM vs SSA/NS (P) Asymptomatic 332 223 34 48 79.6% vs 68.3% (P = 0.015) Symptomatic 96 57 15 23 20.4% vs 31.7% (P = 0.015) HAM/TSP 55 32 5 17 12.5% vs 21.2% (P = 0.04) ATLL 33 19 8 6 7.9% vs 14.6% (P = 0.06) Strongyloides stercoralis 8 6 2 0 2.6% vs 2.4% (ns) ATLL = adult T-cell leukemia/lymphoma; HAM = HTLV-1-associated myelopathy; HTLV-1 = human T-lymphotropic virus type 1; LATAM = Latin America; NS = native Spaniards; SSA = Sub-Saharan Africa; TSP = Tropical spastic paraparesis; 57%), T-cell lymphoma (n = 33; 34%), or Strongyloides stercoralis Discussion infestation (n = 8; 8%). Before 2008, HTLV-1 testing was per- formed only in individuals with clear suspicion of infection, ei- Infection with HTLV-1 is present worldwide with a focus on ther because of symptoms or having had sexual contact or fam- high endemicity in distinct geographical regions and specific in- ily members with HTLV-1. Since 2008, HTLV-1 screening has ex- digenous communities (Gessain and Cassar, 2012; Hirons et al., panded, and diagnoses can be made either at blood banks (44%) or 2021; Legrand et al., 2022). Over their lifetime, only 10% of infected clinics (56%). individuals may develop clinical manifestations (Hirons et al., In this nationwide register, it is noteworthy that native 2021). Although the most characteristic HTLV-1-associated illnesses Spaniards and Sub-Saharan Africans are overrepresented among are HAM and ATLL, a wide range of inflammatory conditions may patients first presenting with HTLV-1-associated illnesses (31.7% vs appear in carriers, including uveitis, arthritis, thyroiditis, and pul- 20.4%, respectively; P = 0.015), suggesting that missing early di- monary diseases (Hirons et al., 2021; Umekita and Okayama, 2020; agnoses which led to the late presentation are more common in Ramos et al., 2020a,2020b). these populations than carriers from LATAM (Table 1). Given that 22% of individuals first presenting with HTLV-1 in- fection in Spain are symptomatic, underdiagnosis must be com- 973 C. de Mendoza, L. Pérez, M. Fernández-Ruiz et al. International Journal of Infectious Diseases 122 (2022) 970–975 mon. Although screening in blood banks has mostly unveiled Barcelona); A. Aguilera & S. Pereira (hospital Conxo-CHUS, San- asymptomatic carriers from LATAM, a disproportionately high tiago); R. Benito, S. Algarate & M. Ducons (hospital clínico uni- number of native Spaniards and Sub-Saharan Africans are diag- versitario lozano Blesa, Zaragoza); S. Rojo. (Valladolid: Hospital nosed too late, when they already have developed classical HTLV-1 Clínico Universitario) (Centro Sanitario Sandoval. Madrid); J.M. illnesses, mostly HAM or ATLL. Eirós (Hospital Rio Hortega, Valladolid); J. García (Hospital Cristal- To date, HTLV antibody screening in Spain is mandatory for all Piñor, Orense); E. Calderón (Hospital Virgen del Rocío & CIBERESP, first-time blood donors from endemic countries. However, some Sevilla); M. Trigo, J. Diz & M. García-Campello (Complejo Hospi- blood centers perform universal HTLV screening regardless of talario, Pontevedra); M. Rodríguez-Iglesias, N. Montiel & T. Tru- country of origin or being a repeated donor. It should be noted that jillo (Hospital Universitario, Puerto Real); A. Hernández-Betancor whereas HTLV-1 screening in Spanish blood banks has mostly un- & A.M. Martín (Hospital Insular Hospital Universitario, Las Pal- veiled asymptomatic HTLV-1 carriers from LATAM, individuals with mas de Gran Canaria); MJ. Pena (Hospital Universitario Dr. Negrín, HTLV-1 infection belonging to other groups either rarely donate Las Palmas de Gran Canaria). J.M. Ramos & I. Escribano (Hospi- blood (i.e., Sub-Saharan Africans because of a history of malaria) or tal Universitario, Alicante); C. Gómez-Hernando (Complejo Hospita- are not tested for the virus (i.e., native Spaniards). Therefore, other lario Virgen de la Salud, Toledo); M. Arazamendi (Hospital Donos- strategies should be implemented to reduce HTLV-1 misrecognition tia, San Sebastián); L. Fernández-Pereira (Hospital San Pedro de Al- in these groups. cántara, Cáceres); M. Hernández, A.M. López-Lirola & J.L. Gómez- HTLV-1 is mostly transmitted sexually, perinatally through Sirvent (Hospital Universitario La Laguna, Tenerife); L. Force (Hos- breastfeeding, and through blood transfusions or transplants. Al- pital General, Mataró); C. Cifuentes (Hospital Son Llátzer, Palma though HTLV-1 screening in Spain is currently performed in blood de Mallorca); S. Pérez & L. Morano (Hospital do Meixoeiro, Vigo); banks and the transplantation setting (de Mendoza et al., 2019), C. Raya (Hospital del Bierzo, Ponferrada); A. González-Praetorius testing of pregnant women (Treviño et al., 2011) and of patients (Hospital Universitario, Guadalajara); MD. Maciá (Hospital Son Es- attending clinics for sexually transmitted infections (STI) is scarce. pases, Mallorca); L. Roc (Hospital Miguel Servet, Zaragoza); I. Vi- The benefit of introducing antenatal HTLV-1 screening derives from ciana (Hospital Virgen de la Victoria, Málaga); T. Cabezas (Hospi- the effectiveness in halting vertical transmission when breastfeed- tal Torredecárdenas, Almeria); A. Lozano, E. Fernández-Fuertes & ing is avoided by HTLV-positive mothers (Paiva et al., 2018). Re- J.M. Fernández (Hospital de Poniente, Almería); I. García-Bermejo garding anti-HTLV screening in STI clinics, several reports have un- & G. Gaspar (Hospital Universitario, Getafe); L. Pérez, M. Valeiro & derlined its cost-effectiveness in sites with a large population com- T. Aldamiz (Hospital Gregorio Marañón, Madrid); E. Miró (Hospi- ing from endemic regions (Caswell et al., 2019). Spain is the Euro- tal Santa Creu i Sant Pau, Barcelona); S. Sauleda & M. Pirón (Banco pean country hosting the largest migrant population from LATAM de Sangre & Tejidos, Barcelona); R. González, A. Richart & L. Barea (1.5 million out of the country’s total 47 million population). (Centro de Transfusiones, Madrid); A. Jiménez & L. Blanco (Centro From 428 individuals with HTLV-1 infection reported in Spain de Hemoterapia y Hemodonación de Castilla y León, Valladolid); I. until the end of 2021, the source of infection could be presumed Rodríguez-Avial (Hospital Clínico San Carlos, Madrid); M. Fernán- confidently for only 207. Sexual transmission was involved in 133 dez, P. Parra, N. Redondo & T. Ruiz (Hospital Universitario 12 de (64%), whereas other routes were less frequent, including vertical Octubre, Madrid); M. Fernández-Alonso & G. Reina (Clínica Uni- in 35 (17%) and throughout transfusion/transplantation in 17 (8%). versitaria Navarra, Pamplona); E. Ugalde, M.C. Nieto & P. Liendo Most of the 71 (17%) native Spaniards infected with HTLV-1 ac- (Hospital Universitario de Basurto); I. Pintos, V. Moreno-Torres, V. knowledged having had a sex partner from LATAM. Finally, from a Cuervas-Mons & C. de Mendoza (IIS Hospital Universitario Puerta total of 22 new diagnoses of HTLV-1 reported in Spain in 2021, 2 de Hierro, Majadahonda); P. Barreiro (La Paz University Hospital, of 13 women were pregnant. Madrid); V. Soriano, A. Treviño, F. Gómez-Gallego & O. Corral (UNIR We should acknowledge several caveats and limitations in our Health Sciences School, Madrid). study. The retrospective recording of epidemiological and clini- cal data has often made collecting detailed information on clini- Ethics cal manifestations and contact tracing to exclude infections in sex partners or other family members difficult. In contrast, the lack of Approval was not required according to Spanish law for studies uniform criteria for HTLV testing across the country may have de- using anonymized databases. termined a different sensitivity to unveil asymptomatic carriers in different regions. Although the yearly estimated number of HTLV Author contributions tests ranges from 20,0 0 0 to 30,0 0 0, there is a large difference be- tween country regions. CdM and VS designed the study, did the initial analyses, and In summary, we report a disproportionately high rate of HTLV- wrote the first draft. All authors reviewed the draft and con- 1 individuals presenting with clinical manifestations in Spain. We tributed comments, suggestions, and further analyses. All authors postulate that the late presentation of HTLV-1 reflects suboptimal recorded information from patients examined in the study. clinical suspicion and supports more broad testing. Given that nei- ther vaccines nor antiviral drugs exist to treat HTLV-1 illnesses and Declarations of competing interest that once the virus is acquired, infection is lifelong, prevention re- mains the most effective weapon to fight this retrovirus. Anti-HTLV The authors have no competing interests to declare. screening of target populations will be cost-effective in regions or communities with a relatively high proportion of individuals from Funding HTLV-1 endemic regions. In Spain, our data support the universal screening of anti-HTLV in pregnant women and in patients who This work was supported in part by grants from FIS-ISCIII PI- attended STI clinics. 21/1717 and Fundación Mutua Madrileña AP-174112020. Members of the Spanish HTLV Network References Araujo A, Bangham CRM, Casseb J, Gotuzzo E, Jacobson S, Martin F, et al. Manage- Ayerdi O, Rodriguez C, del Romero J. M.D. Ocete (hospital gen- ment of HAM/TSP: systematic review and consensus-based recommendations eral universitario, Valencia); A. Rando (hospital Vall d’Hebrón, 2019. Neurol Clin Pract 2021;11:49–56. 974 C. de Mendoza, L. Pérez, M. Fernández-Ruiz et al. International Journal of Infectious Diseases 122 (2022) 970–975 Bangham CR, Araujo A, Yamano Y, Taylor GP. 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