Overview of virus and cancer relationships. Position paper.

The role of certain viruses in the etiology of some tumors is today indisputable, but there is a lack, however, of annoverview of the relationship between viruses and cancer with amultidisciplinary approach. For this reason, the Health Sciences Foundation has convened a group of professionals from different areas of knowledge to discuss the relationship between viruses and cancer, and the present document is the result of these deliberations. Although viruses cause only 10-15% of cancers, advances in oncology research are largely due to the work done during the last century on tumor viruses. The clearest cancer-inducing viruses are: HPV, HBV, HCV, EBV and, depending on the geographical area, HHV-8, HTLV-1 and HIV. HPVs, for example, are considered to be the causative agents of cervical carcinomas and, more recently, of a proportion of other cancers. Among the Herpes viruses, the association with the development of neoplasms is well established for EBV and HHV-8. Viruses can also be therapeutic agents in certain neoplasms and, thus, some oncolytic viruses with selective tropism for tumor cells have been approved for clinical use in humans. It is estimated that the prophylaxis or treatment of viral infections could prevent at least 1.5 million cancer deaths per year.

Queratoconjuntivitis por Vittaforma corneae: una enfermedad emergente entre los viajeros que regresan del sudeste asiático / Vittaforma Corneae keratoconjunctivitis: An emerging pathology among travelers returning from Southeast Asia

La queratoconjuntivitis por Microsporidium es un cuadro infrecuente. Se ha asociado a brotes epidémicos en Asia relacionados con la exposición a agua o tierra contaminada. Habitualmente estos cuadros son autolimitados y leves, pero pueden tener evoluciones prolongadas. Presentamos el caso de una paciente de 29 años que comenzó con dolor, enrojecimiento, visión borrosa en su ojo derecho tras su vuelta de un viaje a Singapur y que no mejoró tras un tratamiento convencional frente a conjuntivitis. Fue diagnosticada de queratoconjuntivitis por Microsporidium mediante PCR y tinción con PAS del epitelio corneal. El tratamiento inicial fue desbridamiento epitelial, albendazol oral y voriconazol, levofloxacino y propamidina, pero la enfermedad conjuntival y corneal no cedió hasta que si introdujeron corticoides tópicos 5 meses después para tratar la limbitis. Debemos tener la sospecha de queratitis por Microsporidium en casos de queratitis unilateral y conjuntivitis, sobre todo en pacientes que vuelvan de Asia

Microsporidium keratoconjunctivitis is an very rare disease. It is related to outbreaks in Asia due to exposure to contaminated water or soil. Microsporidium keratoconjunctivitis is a a self-limited disease, but it could have long term courses. We present the case of a 29 year old woman who started with pain, redness and blurred vision after a holiday in Singapore and did not respond to conjunctivitis treatment. PCR sequencing and PAS staining of corneal epithelial biopsy identified Vittaforma corneae as the causative organism. Treatment was initiated with corneal debridement, oral albendazol, and intensive topical voriconazole, levofloxacin and propamidine, but the conjunctival and corneal disease was only resolved 5 months later with the introduction of topical steroids to treat her severe limbitis. Suspicion of Microsporidium keratoconjunctivitis should be raised amongst ophthalmologists in unilateral keratitis with mild conjunctivitis in travelers from Asia

Vittaforma Corneae keratoconjunctivitis: An emerging pathology among travelers returning from Southeast Asia. / Queratoconjuntivitis por Vittaforma corneae: una enfermedad emergente entre los viajeros que regresan del sudeste asiático.

Microsporidium keratoconjunctivitis is an very rare disease. It is related to outbreaks in Asia due to exposure to contaminated water or soil. Microsporidium keratoconjunctivitis is a a self-limited disease, but it could have long term courses. We present the case of a 29 year old woman who started with pain, redness and blurred vision after a holiday in Singapore and did not respond to conjunctivitis treatment. PCR sequencing and PAS staining of corneal epithelial biopsy identified Vittaforma corneae as the causative organism. Treatment was initiated with corneal debridement, oral albendazol, and intensive topical voriconazole, levofloxacin and propamidine, but the conjunctival and corneal disease was only resolved 5 months later with the introduction of topical steroids to treat her severe limbitis. Suspicion of Microsporidium keratoconjunctivitis should be raised amongst ophthalmologists in unilateral keratitis with mild conjunctivitis in travelers from Asia.

Update on the major imported helminth infections in travelers and migrants.

Helminth infections cause considerable morbidity worldwide and may be frequently underdiagnosed especially in areas of lower endemicity. Patients may harbor latent infections that may become symptomatic years or decades after the initial exposure and timely diagnosis may be critical to prevent complications and improve outcomes. In this context, disease in special populations, such as immunosuppressed patients, may be of particular concern. Heightened awareness and recent diagnostic developments may contribute to the correct management of helminth infections in nonendemic regions. A review of the main helminth infections in travelers and migrants (strongyloidiasis, taeniasis-neurocysticercosis and schistosomiasis) is presented, focusing on epidemiology, developments in diagnosis, treatment and prevention.

Comparison of the toxicity of two treatment schemes with benznidazole for chronic Chagas disease: a prospective cohort study in two Spanish referral centres.

OBJECTIVES: Chagas disease (CD) treatment is limited to two therapeutic options: benznidazole (generally the first option in Spain) and nifurtimox. Both drugs present high rates of adverse reactions and treatment discontinuation and there is no consensus regarding the most effective administration schedule for benznidazole or how to prevent and manage treatment toxicity. We aim to compare the tolerability and treatment discontinuation rate between two different treatment schemes with benznidazole. METHODS: This was a prospective observational study of adult patients with CD, enrolled from January 2014 to March 2018 in two referral centres in Madrid (Spain). Participants were treated either with benznidazole 5 mg/kg/day (full dose) over 60 days (benznidazole standard dose scheme (BSD)), or with an escalating dose lasting 5 days up to a maximum of 300 mg/day (benznidazole increasing dose scheme (BID)). RESULTS: 471 patients were analysed: 201 in the BSD group and 270 in the BID group. There were no significant differences regarding age (40.4 (SD 8.7) vs 41 (SD 8.2) years), sex (74.1% (149/201) vs 68.5% (185/270) women), weight (69.4 (SD 12.8) vs 68.9 (SD 11) kg) or nationality (97.5% (196/201) vs 96.7% (261/270) Bolivians) between groups. There were also no differences in adverse reactions rate (55.2% (111/201) vs 55.6% (150/270)), number of adverse reactions per patient, adverse reactions type (except for arthralgias and myalgias which occurred more frequently in the BID group (0% (0/111) BSD vs 8% (12/150) BID; p 0.002)) and degree and time to first adverse reactions. There was significantly more treatment discontinuation (49.8% (100/201) vs 33.0% (89/270); p <0.001) in the BSD group, but not during the first 30 days of treatment (32.3% (65/201) vs 25.6% (69/270); p 0.08). CONCLUSION: The use of increasing doses of benznidazole for 5 days and a maximum dose of 300 mg, does not significantly improve drug tolerability. However, while the treatment discontinuation rates were similar during the first 30 days of treatment, it may improve the treatment completion rate at 60 days.

Toxicity of nifurtimox as second-line treatment after benznidazole intolerance in patients with chronic Chagas disease: when available options fail.

OBJECTIVE: To describe the tolerability and rate of nifurtimox discontinuation when administered as a second-line treatment to patients with previous treatment interruptions due to adverse reactions with benznidazole. METHODS: We studied a prospective cohort study of adult patients with chronic Chagas disease in a referral centre in Spain treated from July 2007 to July 2017. We analysed the tolerability profile and treatment interruption rate due to adverse reactions (ARs) to nifurtimox in patients previously incompletely treated (less than 30 days) with benznidazole due to ARs. RESULTS: A total of 472 patients initiated treatment with benznidazole during the study period. Of these, 118 (25%) developed ARs that led to treatment discontinuation before 30 days of therapy. Fifty-three (44.9%) of 118 initiated nifurtimox as second-line treatment; most were women (79.3%), were of Bolivian origin (98.1%) and had a median age of 37.3 years (interquartile range, 29.8-43.2). The most common ARs with nifurtimox were cutaneous hypersensitivity (24.1%), digestive disorders (22.2%), fever (12.9%), neurologic disturbances (11.1%), depression, anxiety or insomnia (9.2%), dyspnoea (7.4%), myalgia (5.5%), and dizziness, asthenia or malaise (7.4%). Twenty-six (49.1%) of 53 patients discontinued nifurtimox due to ARs, all of them before the required minimal therapy duration of 60 days. There were no deaths. CONCLUSIONS: Treatment of chronic Chagas disease relies on two drugs with a poor tolerability profile. In our cohort, 12.3% of the patients who initiated benznidazole and subsequently nifurtimox in case of nontolerance developed ARs that led to permanent treatment discontinuation. Most were women of childbearing age, a group for whom therapy has the added benefit of interrupting vertical transmission.

Challenges in the management of Chagas disease in Latin-American migrants in Europe.

Chagas disease is endemic in Latin America. Due to migration the infection has crossed borders and it is estimated that 68,000-120,000 people with Chagas disease are currently living in Europe and 30% of them may develop visceral involvement. However, up to 90% of Chagas disease cases in Europe remain undiagnosed. The challenges which have to be overcome in Chagas disease in non-endemic countries are focused on related downing barriers to health care access, and related to screening, diagnostic tools and therapeutic management. The aim of this review is to highlight how healthcare management for Latin American migrants with Chagas disease in Europe may be improved. Medical literature was searched using PubMed. No limits were placed with respect to the language or date of publication although most of the articles selected were articles published in the last five years. Chosen search terms were "Chagas disease" AND ("migrants" OR "screening" OR "transmission" OR "treatment"; OR "knowledge" OR "non-endemic countries"); migrants AND ("Public health" OR "Health Service Accessibility" OR "Delivery of Health care"); and "Congenital Chagas disease". Healthcare management of migrant populations with Chagas disease in Europe has to be improved: -Surveillance programmes are needed to measure the burden of the disease; -screening programmes are needed; -administrative and cultural barriers in the access to health care for migrants should be reduced; -education programmes on Chagas disease should be performed -research on new diagnostic tools and therapeutic options are required. This review highlights the needs of profound changes in the health care of Latin American migrants with Chagas disease in Europe.

[Diagnosis and treatment of imported eosinophilia in travellers and immigrants: Recommendations of the Spanish Society of Tropical Medicine and International Health (SEMTSI)]. / Diagnóstico y tratamiento de la eosinofilia importada en viajeros e inmigrantes: recomendaciones de la Sociedad Española de Medicina Tropical y Salud Internacional (SEMTSI).

According to published data, prevalence of imported eosinophilia among travellers and immigrants is set between 8% and 28.5%. Etiological diagnosis is often troublesome, and depending on the depth of the study and on the population analyzed, a parasitic cause is identified in 17% to 75.9% of the individuals. Among the difficulties encountered to compare studies are the heterogeneity of the studied populations, the type of data collection (prospective/retrospective) and different diagnostic protocols. In this document the recommendations of the expert group of the Spanish Society of Tropical Medicine and International Health (SEMTSI) for the diagnosis and treatment of imported eosinophilia are detailed.

[Current management of imported severe malaria]. / Abordaje terapéutico actual de la malaria grave importada.

Severe malaria is a diagnostic and therapeutic emergency with great impact worldwide for incidence and mortality. The clinical presentation of severe malaria can be very polymorphic and rapidly progressing. Therefore a correct diagnosis and an early and adequate antiparasitic and support therapy are essential. This paper attempts to outline the diagnosis frame and the treatment of severe malaria for adults, paediatric patients and for pregnant.

[Resistance to the antimalarial drugs]. / Resistencia a los antimaláricos.

Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was described for the first time the resistance to quinine and, since then, drug resistance to antimalarial drugs has spread up to represent a global challenge in the fight and control of malaria. Understanding the mechanisms, geography and monitoring tools that we can act against resistance to antimalarial drugs is critical to prevent its expansion.

CTX-M-15-non-ST131 Escherichia coli isolates are mainly responsible of faecal carriage with ESBL-producing Enterobacteriaceae in travellers, immigrants and those visiting friends and relatives.

Prevalence of extended-spectrum ß-lactamases (ESBL) and/or carbapenemase-producing Enterobacteriaceae (EPE and CPE) in stool samples from 75 travellers, 8 people visiting friends and relatives and 3 immigrants who had travelled or came from tropical or subtropical areas was determined. Thirty-one per cent (27/86) of the subjects were faecal carriers of EPE, and 37 EPE isolates were recovered (36 Escherichia coli, 1 Klebsiella pneumoniae). CTX-M-15 was the most prevalent enzyme (64.8%) mainly associated with E. coli belonging to phylogroup A and sequence type complex 10. Most of the ESBL-positive travellers (50%) had visited countries from Asia.

Leishmaniasis in immunosuppressed individuals.

Leishmaniasis is a vector-born chronic infectious disease caused by a group of protozoan parasites of the genus Leishmania. Whereas most immunocompetent individuals will not develop disease after Leishmania infection, immunosuppression is a well-established risk factor for disease. The most severe form is visceral leishmaniasis (VL), which is typically fatal if untreated. Whereas human immunodeficiency virus (HIV) co-infection (VL-HIV) was initially mainly reported from southern Europe, it is now emerging in other regions, including East Africa, India, and Brazil. VL has also been found in a wide range of non-HIV-related immunosuppressive states, mainly falling under the realm of transplantation medicine, rheumatology, haematology, and oncology. Clinical presentation can be atypical in immunosuppressed individuals, being easily misdiagnosed or mistaken as a flare-up of the underlying disease. The best diagnostic approach is the combination of parasitological and serological or molecular methods. Liposomal amphotericin B is the drug of choice. Treatment failure and relapse rates are particularly high in cases of HIV co-infection, despite initiation of antiretroviral treatment. Primary prophylaxis is not recommended, but secondary prophylaxis is recommended when the patient is immunosuppressed. Cutaneous leishmaniasis can have a number of particular features in individuals with immunosuppression, especially if severe, including parasite dissemination, clinical polymorphism with atypical and often more severe clinical forms, and even visceralization. Mucosal leishmaniasis is more common. Treatment of cutaneous and mucosal leishmaniasis can be challenging, and systemic treatment is more often indicated. With globally increased travel and access to advanced medical care in developing countries, the leishmaniasis burden in immunosuppressed individuals will probably continue to rise, warranting increased awareness and enhanced surveillance systems.

Travelers visiting friends and relatives (VFR) and imported infectious disease: travelers, immigrants or both? A comparative analysis.

INTRODUCTION: Immigrants are increasingly traveling back to their countries of origin to visit friends and relatives (VFRs). They account for an important proportion of all international travelers and have a high risk for certain travel-related infectious diseases. METHODS: We describe the spectrum of infectious diseases diagnosed in a cohort of 351 VFRs and compare them with two previously published cohorts: of immigrants and travelers attended at our centre. RESULTS: The most frequent diagnoses observed among VFRs were typical travel-associated infections such as malaria (75 [21.4%]), traveler's diarrhea 17 [4.8%]), intestinal parasites (16 [4.6%]) and dengue (11 [3.1%]). Asymptomatic chronic infectious diseases, such as latent tuberculosis (56 [16%]), chronic viral hepatitis (18 [5.1%]) and filariasis (18 [5.1%]), probably acquired before migration, were also observed. CONCLUSIONS: VFRs should thus be approached from two perspectives as concerns imported infectious diseases: as travelers and as immigrants. Etiological studies focusing on the presenting complaint as well as systematic screening for other latent infectious diseases should be performed.

Infectious diseases among travellers and migrants in Europe, EuroTravNet 2010.

To investigate trends in travel-associated morbidity with particular emphasis on emerging infections with the potential for introduction into Europe, diagnoses of 7,408 returning travellers presenting to 16 EuroTravNet sites in 2010 were compared with 2008 and 2009. A significant increase in reported Plasmodium falciparum malaria (n=361 (6% of all travel-related morbidity) vs. n=254 (4%) and 260 (5%); p<0.001), P. vivax malaria (n=51 (1%) vs. n=31 (0.5%) and 38 (1%); p=0.027) and dengue fever (n=299 (5%) vs. n=127 (2%) and 127 (2%); p<0.001) was observed. Giardia lamblia was identified in 16% of patients with acute diarrhoea, with no significant annual variation. The proportion of acute diarrhoea due to Campylobacter increased from 7% in 2008 to 12% in 2010 (p=0.001). We recorded 121 patients with pulmonary tuberculosis in 2010, a threefold increase in the proportionate morbidity from 2008 to 2010. In 2010, 60 (0.8%) cases of chronic Chagas disease, 151 (2%) cases of schistosomiasis and 112 (2%) cases of cutaneous larva migrans were reported. Illness patterns in sentinel travellers, captured by EuroTravnet, continue to highlight the potential role of travellers in the emergence of infectious diseases of public health concern in Europe and the relevance of offering medical travel advice and enforcing specific and adequate prophylaxis.

Travel-related imported infections in Europe, EuroTravNet 2009.

The aim of this study was to investigate travel-associated morbidity in European travellers in 2009 in comparison with 2008, with a particular emphasis on emerging infectious diseases with the potential for introduction into Europe. Diagnoses with demographic, clinical and travel-related predictors of disease from ill returning travelers presenting to 12 core EuroTravNet sites from January to December 2009 were analysed. A total of 6392 patients were seen at EuroTravNet core sites in 2009, as compared with 6957 in 2008. As compared with 2008, there was a marked increase in the number of travellers exposed in North America and western Europe. Respiratory illnesses, in particular pandemic A(H1N1) influenza, influenza-like syndromes, and tuberculosis, were also observed more frequently. A significant increase in reported dengue cases in 2009 as compared with 2008 was observed (n = 172, 2.7% vs. n = 131, 1.90%) (p 0.002). The numbers of malaria and chikungunya cases were also increasing, although not significantly. Two deaths were recorded: visceral leishmaniasis and sepsis in a Sudanese migrant, and Acinetobacter sp. pneumonia in a patient who had visited Spain. This is the most comprehensive study of travel-related illness in Europe in 2009 as compared with 2008. A significant increase in travel-related respiratory and vector-borne infections was observed, highlighting the potential risk for introduction of these diseases into Europe, where competent vectors are present. The number of traveller deaths is probably underestimated. The possible role of the travellers in the emergence of infectious diseases of public health concern is highlighted.

Lack of association between blood-based detection of Trypanosoma cruzi DNA and cardiac involvement in a non-endemic area.

Cases of chronic Chagas disease have been increasing in non-endemic areas due to the growth in immigration. This study examined the association between positive Trypanosoma cruzi-DNA detection in blood by PCR and presence of chagasic cardiac involvement in a cohort of immigrants in a European city. No association was found in this study between the positive T. cruzi blood PCR and cardiac involvement.

Targeted screening and health education for Chagas disease tailored to at-risk migrants in Spain, 2007 to 2010.

Chagas disease is endemic in Latin America, but migration has expanded the disease's geographical limits. Spain is the most affected country in Europe. From 2007, a specific Chagas disease programme aimed at at-risk migrants was developed in three Spanish cities (Madrid, Jerez de la Frontera and Alicante). The objectives of the programme were to increase participants' knowledge and decrease their fears about the disease and to encourage them to undergo screening for Trypanosoma cruzi infection. The programme was specially focused on migrants from Bolivia and Latin American women of childbearing age. Culturally tailored interventions were carried out in non-clinical settings. A total of 276 migrants were screened using a rapid immunochromatographic test following talks on the disease: the results were then later confirmed by standard serological tests. Of those tested, 44 (15.9%) were confirmed cases of Chagas disease. All of them came from Bolivia and a quarter were pregnant women. Of the 44 cases, 31 were later followed up at a specialised Chagas disease clinic. We consider that the adaptation of the programme to the target population's needs and collaboration with non-governmental organisations and migrants' associations contributed to the acceptance of the programme and the increasing number of patients seen at a specialised clinic.