Open Forum Infectious Diseases BRIEF REPORT Clinical Presentation of Individuals Human T-cell leukemia virus type 1 (HTLV-1) was the first dis- covered human retrovirus. It was isolated 50 years ago from a With Human T-Cell Leukemia Virus patient with a cutaneous T-cell lymphoma [1]. Approximately Type-1 Infection in Spain 10–15 million people are estimated to be chronically infected with HTLV-1 worldwide [2, 3]. Highly endemic regions exist Carmen de Mendoza,1 Maria Pirón,2 Rocío Gonzalez,3 Ana Jiménez,4 Estrella Caballero,5 Lourdes Roc,6 Rafael Benito,7 Jose Manuel Ramos,8 and in the Caribbean and parts of Latin America, West Africa, Vicente Soriano9,10; on behalf of the HTLV Spanish Study Group Iran, Japan, and Romania. Within the European Union, most 1 Puerta de Hierro Research Institute and University Hospital, Majadahonda, Madrid; 2Blood HTLV-1 infections are made in persons with black ethnicity and Tissue Bank, Barcelona; 3Regional Transfusion Center, Madrid; 4Centro de Hemoterapia de Castilla-León, Valladolid; 5Hospital Vall d’Hebrón, Barcelona; 6Hospital Miguel Servet, from coming from either the Caribbean or sub-Saharan Africa Zaragoza; 7Hospital Clínico Universitario Lozano Blesa, Zaragoza; 8General Hospital, Alicante; [2–4]. The virus is mostly transmitted sexually [5], perinatally Downloaded from https://academic.oup.com/ofid/article/6/2/ofz036/5290444 by guest on 27 November 2023 9 UNIR Health Sciences School, Madrid; and 10La Paz University Hospital, Madrid, Spain by breastfeeding [6], and parenterally throughout contaminated Background. Although only 8%–10% of persons infected blood either after transfusions or needle sharing among injec- with human T-cell leukemia virus type 1 (HTLV-1) may de- tion drug users [7, 8]. velop virus-associated diseases lifelong, misdiagnosis of asymp- Only 8%–10% of persons infected with HTLV-1 may develop tomatic infected carriers frequently leads to late diagnoses. 2 characteristic-associated diseases [9–11]—namely, tropical Methods. A nationwide HTLV-1 register was created in spastic paraparesis (TSP), or HTLV-associated myelopathy Spain in 1989. A total of 351 infected persons had been reported (HAM), and adult T-cell leukemia/lymphoma (ATL)—during by the end of 2017. We examined all new HTLV-1 diagnoses their lifetime. Misdiagnosis of asymptomatic HTLV-1 carriers during the last decade and compared their clinical presentation. frequently leads to late diagnoses. In this regard, the real burden Results. A total of 247 individuals with HTLV-1 infection had of HTLV-1 infections in a region may be indirectly inferred from been reported in Spain since year 2008. The incidence has remained stable with 20–25 new diagnoses yearly. Women represented 62%. the number of people presenting with symptomatic illnesses. Only 12% were native Spaniards, most of whom were foreigners from Latin America (72.5%). Up to 57 (23%) individuals presented METHODS clinically with HTLV-1-associated conditions, including subacute A nationwide HTLV-1 register and biological repository was myelopathy (n = 24; 42.1%), T-cell lymphoma (n = 19; 33.3%), or created in Spain since 1989. More than 45 centers are members Strongyloides stercoralis infestation (n = 8; 14%). Human T-cell of the Spanish HTLV Network, distributed across the whole leukemia virus type 1 diagnosis had been made either at blood banks (n = 109; 44%) or at clinics (n = 138; 56%). It is interesting to national geography. Participating centers and major epidemi- note that Spaniards and especially Africans were overrepresented ological findings have already been described elsewhere [12]. among patients presenting with HTLV-1-associated illnesses, sug- Uniform case report forms collecting demographics, epidemio- gesting that misdiagnosis and late presentation are more frequent logical features, clinical signs, and manifestations are filled out in these populations compared to Latin Americans. for each new diagnosis by the respective doctor in charge. On a Conclusions. Given that 23% of new HTLV-1 diagnoses yearly basis, a group meeting is arranged around mid December in Spain are symptomatic, underdiagnosis must be common. and new cases are presented and discussed by all members of Although screening in blood banks mostly identifies asymp- the network. tomatic Latin American carriers, a disproportionately high Human T-cell leukemia virus testing in Spain is conducted number of Spaniards and Africans are unveiled too late, that is, at the microbiology departments of clinics/hospitals on de- they already suffer from classic HTLV-1 illnesses. mand, only when there is clinical suspicion, and rarely as part Keywords. adult T-cell leukemia; epidemiology; HTLV-1; of general screening for sexually transmitted infections or pre- myelopathy; screening. natal testing. In contrast, HTLV antibodies are examined man- datorily in all transplants as well as in at-risk blood donors. Received 18 November 2018; editorial decision 13 January 2019; accepted 15 January 2019. Individuals diagnosed with HTLV-1 at blood banks are initially Correspondence: V. Soriano, MD, PhD, UNIR Health Sciences School, Calle Almansa 101, Madrid 28040, Spain (vicente.soriano@unir.net). informed by the transfusion center medical staff and invited to Open Forum Infectious Diseases® attend appointments with infectious diseases specialists that are © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases associated with the Spanish network at clinics located at dif- Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ ferent large cities. by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any A total of 351 individuals with HTLV-1 infection had been medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com reported in Spain by the end of 2017. For the purpose of this DOI: 10.1093/ofid/ofz036 study, we examined the clinical presentation of all persons with BRIEF REPORT • ofid • 1 HTLV-1 infection diagnosed only during the last decade. Expert The main characteristics of these 2 populations are recorded in clinicians reviewed clinical charts and checked neurological Table 1. Spaniards and especially Africans were overrepresented and hematological signs/symptoms in particular. When pos- among hospital-based HTLV-1 diagnoses, suggesting that late sible, epidemiological information was tracked to determine presentation and misdiagnosis were more common in these 2 the most likely routes of HTLV-1 transmission. groups compared with Latin Americans. Table 2 records the main features of 57 HTLV-1-infected Statistical Analysis patients presenting with symptomatic illnesses, which were All numerical variables are reported as absolute values and mostly neurological (61%) or hematological conditions (33%). percentages. Categorical variables were compared using χ2 or Women were more frequently represented than men (65%), re- Fisher exact tests, whereas noncategorical variables were com- gardless of clinical presentation. On the other hand, individuals pared using Student t test or Mann-Whitney U tests. All analy- presenting with TSP/HAM were on average 8 years older than ses were 2-tailed, and only P values below .05 were considered those with ATL. Finally, although Spaniards presented more to be significant. All statistical analyses were performed using frequently with TSP/HAM than ATL (8 vs 2), the opposite Downloaded from https://academic.oup.com/ofid/article/6/2/ofz036/5290444 by guest on 27 November 2023 SPSS software, version 16.0 (SPSS Inc., Chicago, IL). occurred among Africans (3 vs 5). It is interesting to note that a 54-year-old woman developed RESULTS rapid-onset subacute paraparesis after kidney transplantation A total of 247 individuals with HTLV-1 infection had been re- in 2015 from a cadaveric donor retrospectively known to be ported in Spain since 2008. Most cases were diagnosed around HTLV-1 positive [13]. In contrast, the recipient of the second large urban areas (Madrid and Barcelona) where the largest im- kidney experienced early graft rejection that required surgical migrant populations live. Women represented 62%. Only 12% removal. The recipient discontinued immunosuppressants, and were native Spaniards, most of whom were foreigners from more than 2 years later he remains asymptomatic despite having Latin America (72.5%). Africans represented 8.5%. It is in- been infected with HTLV-1. teresting to note that heterosexual exposure is the most likely source of HTLV-1 infection among native Spaniards, in most DISCUSSION cases this was linked to partners from endemic regions in Latin America. A total of 247 individuals with HTLV-1 infection have been During this period, 57 (23%) individuals presented clini- diagnosed in Spain during the last decade. The large immigrant cally with HTLV-1-associated conditions, including TSP/HAM flow from HTLV-1-endemic regions mostly accounts for this (n = 24; 42.1%), ATL (n = 19; 33.3%), and Strongyloides ster- population, although native Spaniards represent 12% of cases. coralis infestation (n = 8; 14%), or other potentially linked con- Overall, the relatively large proportion of symptomatic indi- ditions, such as neuropathies, sicca syndrome, etc. In 4 (7%) of viduals (23.1%) suggests that HTLV-1 infection is frequently these symptomatic individuals, HTLV-1 was found as coinfec- underdiagnosed in Spain. tion with human immunodeficiency virus-1. Screening in Spanish blood banks mostly identified asymp- One hundred nine subjects (44%) subjects were diagnosed tomatic Latin American carriers, whereas classic HTLV-1- with HTLV-1 at blood banks, and 138 (56%) subjects were diag- associated conditions such as TSP/HAM and ATL unexpectedly nosed at clinics. As expected, blood donors with HTLV-1 infec- unveiled a disproportionately high number of HTLV-1 infec- tion were all asymptomatic, whereas 57 (41%) patients identified tions among Spaniards and Africans. In native Spaniards, at clinics had HTLV-1-associated conditions at presentation. late HTLV-1 diagnoses could largely be due to poor clinical Table 1. New HTLV-1 Diagnoses in Spain (2008–2017) Variables Total Blood Donors Clinics P N (%) 247 109 (44) 138 (56) n.s. Female gender (%) 153 (62) 69 (63) 84 (61) n.s. Median age (years) 43.4 42.6 44 n.s. Country of Origin (%) • Spain 29 (12) 9 20 .09 • Latin America 179 (72.5) 88 91 n.s. • Africa 21 (8.5) 1 20 <.01 • Others 18 (7.3) 11 7 n.s. HTLV symptomatic disease (%) 57 (23) 0 57 (41) <.01 HIV coinfection 4 (1.6) 0 4 (3) <.01 Abbreviations: HIV, human immunodeficiency virus; HTLV, human T-cell leukemia virus type 1; n.s., nonsignificant. 2 • ofid • BRIEF REPORT Table 2. Main Features of 57 Patients Presenting with HTLV-1 Symptomatic Illnesses in Spain (2008–2017) Variables TSP/HAM ATL Othersa P N (%) 24 (42.1) 19 (33.3) 14 (24.6) n.s. Female gender (n) 17 11 10 n.s. Mean age (years) 52.1 44.6 49.8 n.s. Country of Origin (n) • Latin America 13 12 11 n.s. • Africa 3 5 1 n.s. • Spain 8 2 1 n.s. • Others 0 0 1b n.s. HIV coinfection (n) 0 0 4 n.s. Abbreviations: ATL, adult T-cell leukemia/lymphoma; HAM, human T-cell leukemia virus-associated myelopathy; HIV, human immunodeficiency virus; HTLV, human T-cell leukemia virus type 1; N, number; n.s., nonsignificant; TSP, tropical spastic paraparesis. a Strongyloides stercoralis infestation (8), neuropathies other than TSP/HAM (6), sicca syndrome (3), etc. Downloaded from https://academic.oup.com/ofid/article/6/2/ofz036/5290444 by guest on 27 November 2023 b Romania. suspicion in persons that had acquired the virus locally after experienced early organ rejection and discontinued immuno- sexual contacts with Latin Americans [14, 15]. This finding sup- suppressants has remained asymptomatic to date despite be- ports that HTLV-1 should no longer be neglected, and testing coming infected with HTLV-1. should be promoted at clinics for sexually transmitted infec- We should acknowledge several limitations of our study. tions [16]. In Africans, limited access to health services along First, given its retrospective study design, we could not be cer- with poor clinical and epidemiological suspicion in persons tain about the route of infection for a subset of individuals, coming from endemic regions might have contributed to fre- and, likewise, some epidemiological information was missing. quent HTLV-1 misdiagnosis. Moreover, Africans are generally Second, given the voluntary reporting system, we could not excluded in blood banks due to high rates of prior history of totally exclude that some HTLV-1-positive persons diagnosed malaria and other tropical conditions. Therefore, they rarely in Spain were not counted. However, we have a relatively good would be identified as asymptomatic HTLV-1 blood donors. surveillance system, and we actively search and try to contact More than half of new HTLV-1 diagnoses in Spain during those doctors and departments where potential HTLV-1 cases the last decade were performed at clinics. Up to 41% of these or their relatives are medically attended. patients had typical HTLV-1-associated illnesses, that is, either CONCLUSIONS neurological or hematological conditions. Women were more frequently represented than men, regardless of clinical pre- In summary, our results show that the incidence of new HTLV-1 sentation. On average, individuals presenting with TSP/HAM infections in Spain during the last decade has remained rela- were older than those with ATL. It is interesting to note that tively stable at approximately 20–25 cases per year. Although Spaniards more frequently presented with TSP/HAM than Latin Americans and Africans represent more than 80% of cases, ATL, whereas Africans presented with ATL more often than 12% of new HTLV-1 diagnoses are native Spaniards. Moreover, with TSP/HAM. This finding is in agreement with the fact that Spaniards represent approximately 20% of all symptomatic HTLV-1-associated leukemias/lymphomas mostly develop in HTLV-1 diagnoses. Altogether, late presentation and misdiag- subjects infected perinatally from their mothers in highly en- nosis should encourage wider HTLV-1 testing in Spain. Lessons demic regions [17, 18]. Sexual transmission was by far the most from Spain may well apply to other countries with similar large likely route of HTLV-1 infection among native Spaniards. immigration flows from Latin America. Human T-cell leukemia To date, 4 individuals in the Spanish register had developed virus screening should be particularly favored in the following rapid-onset subacute myelopathy after solid organ transplanta- populations: (1) blood donors, given the relatively high number tion from 2 separate donors retrospectively known to be HTLV- of Latin Americans coming from HTLV-1-endemic regions; (2) 1-positive. The first organ donor was reported in year 2000. He solid organ transplantation, given the frequent and high risk of was a young male Spaniard, asymptomatic, with a Venezuelan rapid clinical progression [20, 21]; and pregnant women, given mother who most likely transmitted the infection perinatally. that perinatal HTLV-1 transmission to newborns can be effec- All 3 recipients of the 2 kidneys and the liver, respectively, devel- tively avoided if breastfeeding is discouraged [15]. oped TSP within 18 months [19]. 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