Identification of Chagas disease biomarkers using untargeted metabolomics.

Untargeted metabolomic analysis is a powerful tool used for the discovery of novel biomarkers. Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical disease that affects 6-7 million people with approximately 30% developing cardiac manifestations. The most significant clinical challenge lies in its long latency period after acute infection, and the lack of surrogate markers to predict disease progression or cure. In this cross-sectional study, we analyzed sera from 120 individuals divided into four groups: 31 indeterminate CD, 41 chronic chagasic cardiomyopathy (CCC), 18 Latin Americans with other cardiomyopathies and 30 healthy volunteers. Using a high-throughput panel of 986 metabolites, we identified three distinct profiles among individuals with cardiomyopathy, indeterminate CD and healthy volunteers. After a more stringent analysis, we identified some potential biomarkers. Among peptides, phenylacetylglutamine and fibrinopeptide B (1-13) exhibited an increasing trend from controls to ICD and CCC. Conversely, reduced levels of bilirubin and biliverdin alongside elevated urobilin correlated with disease progression. Finally, elevated levels of cystathionine, phenol glucuronide and vanillactate among amino acids distinguished CCC individuals from ICD and controls. Our novel exploratory study using metabolomics identified potential biomarker candidates, either alone or in combination that if confirmed, can be translated into clinical practice.

Imported schistosomiasis in travelers: Experience from a referral tropical medicine unit in Barcelona, Spain.

BACKGROUND: Acute schistosomiasis occurs most often in travelers to endemic regions. The aim of the study is to describe the epidemiological, clinical and parasitological characteristics of patients with schistosomiasis acquired during an international travel. METHODS: Observational retrospective study including all travel-related schistosomiasis cases seen at the International Health Unit Vall d'Hebron-Drassanes (Barcelona, Spain) from 2009 to 2022. Diagnosis of schistosomiasis was defined by the presence of Schistosoma eggs in stools or urine or the positivity of a serological test. We collected demographic, epidemiological, clinical, parasitological, and therapeutic information. RESULTS: 917 cases of schistosomiasis were diagnosed, from whom 96 (10.5 %) were travel-related. Mean age of the patients was 34.9 years, and 53.1 % were women. Median duration of the travel was 72 days, and geographical areas where travelers had contact with fresh water were Africa (82.3 %), Asia (12.5 %), and South America (5.2 %). Twenty (20.8 %) patients reported having had some clinical symptom, being gastrointestinal symptoms the most frequent. Two patients developed the classical Katayama syndrome. In eleven (11.5 %) cases eggs were observed in urine or feces samples, and 85 (88.5 %) cases were diagnosed by a positive serology. Ninety-one (94.8 %) patients received treatment with praziquantel with different therapeutic schemes. The two patients with Katayama syndrome received concomitant treatment with corticosteroids. CONCLUSIONS: Schistosomiasis in travelers represented 10 % of the overall schistosomiasis cases in our center. Increasing the awareness in the pre-travel advice and implementing specific screening in those travelers at risk (long travelers, contact with fresh water) could reduce the incidence and associated morbidity in this group.

A difficult to treat Leishmania infantum relapse after allogeneic stem cell transplantation.

Here we describe a complicated case of a relapsed Leishmania infantum infection after an allogeneic stem cell transplantation (allo-SCT) for primary myelofibrosis. Three years earlier the patient had been diagnosed with a hemophagocytic lymphohistiocytosis secondary to a visceral Leishmania infantum infection, for which he was effectively treated with a cumulative dose of 40 mg/kg liposomal amphotericin B. During the first disease episode he was also diagnosed with primary myelofibrosis for which he received medical follow-up. One year later ruxolitinib was started due to progressive disease. No Leishmania relapse occurred. Nevertheless, the marrow fibrosis progressed, and an allo-SCT was performed. Two months after allo-SCT prolonged fever and a persistent pancytopenia occurred, which was due to a relapse of visceral Leishmaniasis. The infection was refractory to a prolonged treatment with liposomal amphotericin B with a cumulative dose up to 100 mg/kg. Salvage treatment with miltefosine led to reduction of fever within a few days and was followed by a slow recovery of pancytopenia over the following months. The Leishmania parasite load by PCR started to decline and after 3.5 months no Leishmania DNA could be detected anymore and follow-up until ten months afterwards did not show a relapse.

Opportunistic Community Screening of Chronic Chagas Disease Using a Rapid Diagnosis Test in Pharmacies in Barcelona (Catalonia, Spain): Study Protocol and Pilot Phase Results.

Objectives: This study aimed to report the protocol and results from the pilot phase of an opportunistic CP-based CD screening program in Barcelona, Spain. Methods: Three strategies according to recruitment approach were designed: passive, active and active-community. The study process consisted of signing the informed consent form, recording the patient's data in a web-based database system, and performing the rapid test and blood collection on dry paper. Results: Nineteen pharmacies participated and 64 patients were included during the pilot phase of the study. The rapid diagnostic test (RDT) was positive in 2/64 (3.13%) cases. Of the 49 DBS samples that arrived at the laboratory, 22 (45%) were collected incorrectly. After quantitative and qualitative assessment of the program, the dry paper sample and passive strategy were ruled out. Conclusion: DBS sampling and the passive strategy are not suitable for CD screening in community pharmacies. There is a need to expand the number of participating pharmacies and individuals to determine whether conducting a RDT in community pharmacies is an effective screening method to increase access to CD diagnosis in a non-endemic area.

Frequency and characteristics of HTLV in migrants: results from the +Redivi collaborative network in Spain.

INTRODUCTION: The objective of this study was to describe the main characteristics of migrants diagnosed with human T-lymphotropic virus (HTLV) infection within the +Redivi Spanish network. METHODS: Patients with a diagnosis of HTLV type 1 or 2 in +Redivi from October 2009 to December 2020 were included. Diagnosis was based on positive HTLV serology (enzyme-linked immunosorbent assay (ELISA)/chemiluminescent immunoassay (CLIA)) with line immunoassay (LIA)/Western blot with/without polymerase chain reaction (PCR). RESULTS: A total of 107/17 007 cases (0.6%) had a final diagnosis of HTLV infection: 83 (77.67%) HTLV-1 infections, 6 (5.6%) HTLV-2 infections and 18 (16.8%) non-specified. The majority (76, 71%) were female, median age was 42 years and median time from arrival to Spain until consultation was 10 years. The group included 100 (93.5%) immigrants and 7 (6.6%) visiting friends and relatives (VFR)-immigrants. Most patients were from South America (71, 66.4%), followed by Sub-Saharan Africa (15, 14%) and Central America-Caribbean (13, 12.1%). Around 90% of patients were asymptomatic at presentation and diagnosed as part of screening programs. Median duration of follow-up was 5 years (IQR 2-7). Regarding HTLV-associated conditions, 90 patients (84.2%) had none, 7 (6.5%) had tropical spastic paraparesis , 5 (4.7%) had other associated conditions (dermatitis, uveitis, pulmonary disease), 3 (2.8%) had other neurological symptoms and 2 (1.9%) had adult T-cell leukaemia/lymphoma. No patients with HTLV-2 had HTLV-associated conditions. Four patients (3.7%) died. Concomitant diagnoses were found in 41 (38.3%) patients, including strongyloidiasis in 15 (14%) and HIV co-infection in 4 (3.7%). In 70% of patients, screening of potential contacts was not performed/recorded. CONCLUSIONS: HTLV infections (the majority due to HTLV-1) were mainly diagnosed in asymptomatic migrants from Latin America (generally long-settled immigrants and the majority female with the consequent implications for screening/prevention). A high rate of association with strongyloidiasis was found. In the majority, screening of potential contacts was not performed, representing a missed opportunity for decreasing the under diagnosis of this infection.

Usefulness of the FDG PET/CT in the management of cystic echinococcosis: A pilot study.

OBJECTIVES: Cystic echinococcosis is a zoonotic disease caused by the cestode Echinococcus granulosus. The activity of the cysts is assessed through the WHO-IWGE standardized classification based on ultrasound features. However, viability of the cysts is not always concordant with the activity assessed by ultrasound. The aim of the present study is to describe the metabolic activity of cysts in patients with cystic echinococcosis through FDG-PET. METHODS: Prospective observational study where adult patients diagnosed of cystic echinococcosis were offered to undergo FDG PET/CT before treatment onset. Demographic, clinical, radiological, and histopathological information was collected from all patients. RESULTS: Sixteen patients were included, 50% were male, and age ranged from 18 to 85 years. Most of the patients had liver involvement, and all patients had CE3, CE4 or CE5 stage of the WHO-IWGE classification. Only one patient (CE5) had an increased 18F-FDG uptake of the cyst in the FDG PET/CT. From the 5 patients who underwent surgical treatment, only one showed signs of viability of the cyst: a patient with CE5 with no increased 18F-FDG uptake of the cyst. CONCLUSION: In our pilot study, we did not find the correlation between the FDG PET/CT imaging and the cystic echinococcosis cyst bioactivity.

GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels.

A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) levels as cis methylation quantitative trait loci (cis-mQTL) within this region. A total of 2,611 SNPs were tested against 2,647 DNAm sites, in a subset of 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals from the GWAS. We identified 6,958 significant cis-mQTLs (False Discovery Rate [FDR]<0.05) at 1 Mb each side of the GWAS leading variant, where six of them potentially modulate the expression of the SAC3D1 gene, the reported gene in the previous GWAS. In addition, a total of 268 cis-mQTLs showed differential methylation between chronic Chagas cardiomyopathy patients and asymptomatic individuals. The most significant cis-mQTLs mapped in the gene bodies of POLA2 (FDR = 1.04x10-11), PLAAT3 (FDR = 7.22x10-03), and CCDC88B (FDR = 1.89x10-02) that have been associated with cardiovascular and hematological traits in previous studies. One of the most relevant interactions correlated with hypermethylation of CCDC88B. This gene is involved in the inflammatory response, and its methylation and expression levels have been previously reported in Chagas cardiomyopathy. Our findings support the functional relevance of the previously associated genomic region, highlighting the regulation of novel genes that could play a role in the chronic cardiac form of the disease.

Utility of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Visceral Leishmaniasis: Case Report and Literature Review.

The diagnosis of visceral leishmaniasis (VL) is complicated and often unsuspected. Little is known of the usefulness of nuclear imaging in VL. Our objective was to describe findings seen in fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in cases of VL. We retrospectively reviewed VL cases diagnosed at Vall d'Hebron University Hospital from May 2012 to May 2018 and selected those that had an FDG-PET/CT performed. Information on procedures and details of the FDG-PET/CT features and follow-up were collected. We then systematically reviewed the literature on VL and FDG-PET/CT. Four of 43 patients diagnosed with VL had an FDG-PET/CT performed. All four patients presented diffuse splenic uptake of FDG-PET/CT. Adenopathy was not always present, and bone marrow uptake was found in two patients. A posttreatment FDG-PET/CT in one patient revealed normalization of initial findings. In the literature review, 43 of 50 cases presented similar splenic uptake in the PET/CT, being described as different patterns: "increased metabolism," "homogeneous," "diffuse," "diffuse and multifocal," "nodular," "patchy and granular," "subcortical," and "compatible with lymphoma." Other frequent findings were bone marrow uptake and adenopathies. We, therefore, conclude that FDG-PET/CT could become a useful tool for the diagnosis and follow-up of VL and that VL should be taken into account in patients with fever of unknown origin with enhanced splenic uptake in FDG-PET/CT. Differential diagnosis in these cases should be made with splenic primary lymphoma, virus infections, chemotherapy, and colony-stimulating factor therapy. Further structured studies with more cases are needed to define its diagnostic and prognostic value.

Imported cystic echinococcosis in Spain: a systematic review.

BACKGROUND: Cystic echinococcosis (CE) is a zoonosis caused by Echinococcus granulosus (sensu lato). It is a neglected tropical disease with a global distribution, affecting an estimated 2-3 million people globally. Official reporting systems in Spain lack information concerning imported cases and their country of origin. METHODS: This is a systematic review of the literature that was performed to obtain published cases of immigrant patients diagnosed with CE in Spain. RESULTS: From the 21 included articles, a total of 84 cases of CE imported into Spain were documented from 1995 to 2018, with an average age of 33.2 years. The main countries of origin of the patients were Morocco with 30 cases (35.7%), Romania with 12 cases (14.3%) and Peru with 8 cases (9.5%). The most involved organ was the liver (28 cases [33.3%]). We found discrepancies between the published cases of imported CE in Spain and those reported by official authorities. CONCLUSIONS: This review of the literature shows the lack of information and clarity in the mechanisms of CE notification in Spain. The disparity between these systems and the cases documented in the literature highlights a failure or shortcoming of the current reporting system.

Lack of Association of IL6 polymorphism with the susceptibility to Chagas disease in Latin American populations.

The aim of the present study was to analyze IL6 rs1800795 genetic variant in the susceptibility to Trypanosoma cruzi infection and in the development of chronic Chagas cardiomyopathy (CCC), in five independent Latin American cohorts. A total of 3,087 individuals from Latin American countries (Argentina, Bolivia, Peru, and two cohorts from Colombia) were studied. In all cohorts, patients were classified as seropositive for T. cruzi antigens (n= 1,963) and seronegative (n= 1,124). Based on clinical evaluation, the seropositive patients, were classified as CCC (n= 900) and asymptomatic (n= 1,063). No statistically significant differences in the frequency of IL6 rs1800795 between seropositive and seronegative, or between CCC and asymptomatic patients, were found. Furthermore, after the meta-analysis no statistically significant differences were observed. Our results do not support a contribution of IL6 rs1800795 genetic variant in the susceptibility to the infection and the development of chronic Chagas cardiomyopathy in the studied populations.

Imported cysticercosis in Spain: A retrospective case series from the +REDIVI Collaborative Network.

BACKGROUND: Neurocysticercosis (NCC) is the most common parasitic neurological disease worldwide and a major cause of epilepsy. Spain is the country reporting the highest number of NCC imported cases in Europe. METHODOLOGY: Retrospective case series of NCC patients registered in the +REDIVI Network from October 1, 2009 to July 2018. A specific questionnaire, including clinical and diagnostic characteristics, was created and sent to the collaborator centers. RESULTS: 46 cases were included in the analysis. 55% were male, mean age of 40 years. 95.6% were migrants. The median duration since migration from an endemic area was 10 years. Predominant nationalities were Ecuadorians (50%) and Bolivians (30.4%). Frequent locations were parenchymal (87%), subarachnoid (26.1%) and intraventricular cysts (10.9%). Serological analysis was performed in 91.3%, being 54.8% positive. Most prevalent clinical manifestations were persistent headache (60.9%), epilepsy (43.5%) and visual changes (13%). Patients were mainly treated with albendazole (76.1%), corticosteroids (67.4%), and anticonvulsionants (52.2%). 82.5% had a favorable clinical outcome. CONCLUSIONS: Most NCC cases were long-standing migrants. Few clinical differences were observed depending on the cysticerci location. The treatment was often not according to current recommendations, and no uniform criteria were followed when it came to the therapeutic regimen. NCC case management in Spain (including clinician awareness and laboratory capacity improvements) needs to be strengthened.

Strongyloidiasis screening in migrants living in Spain: systematic review and meta-analysis.

OBJECTIVES: To provide information regarding the prevalence of strongyloidiasis among migrants coming from Strongyloides stercoralis-endemic areas who reside in Spain. METHODS: Systematic review of the literature and meta-analysis of studies showing prevalence of S. stercoralis infection among migrants from Latin America, Africa, Eastern Europe, Asia and Oceania who reside in Spain. We included articles published until 30 April 2019 without language restriction. The keywords used for the search included 'Strongyloides stercoralis', 'strongyloidiasis', 'Spain', 'screening' and 'migrants'. RESULTS: Twenty-four studies were included in the review and meta-analysis, comprising 12 386 screened people. Eleven studies (7020 patients) evaluated the presence of S. stercoralis infection only through investigation of larvae in faeces, showing an overall prevalence of 1% (95%CI 1-1%). Thirteen studies (5366 patients) used a serological test, showing an overall prevalence of 14% (95%CI 11-17%). Strongyloidiasis seroprevalence was 20% (95%CI 15-24%) among migrants from sub-Saharan Africa, 14% (95%CI 10-18%) among those from Latin America and 8% (95%CI 5-11%) among migrants from North Africa. CONCLUSIONS: Migrants coming from strongyloidiasis-endemic areas living in Spain had a high S. stercoralis infection prevalence, particularly those from sub-Saharan Africa and Latin America. This population should be screened using serology as the most sensitive test for S. stercoralis infection. This could be easily implemented at primary care level.

OBJECTIFS: Fournir des informations sur la prévalence de la strongyloïdose parmi les migrants résidant en Espagne et provenant de zones endémiques pour Strongyloides stercoralis. MÉTHODES: Revue systématique de la littérature et méta-analyse des études montrant la prévalence de l'infection à S. stercoralis parmi les migrants d'Amérique latine, d'Afrique, d'Europe de l'Est, d'Asie et d'Océanie qui résident en Espagne. Nous avons inclus des articles publiés jusqu'au 30 avril e 2019 sans restriction de langue. Les mots clés utilisés pour la recherche comprenaient "Strongyloides stercoralis", "strongyloïdose", "Espagne", "dépistage" et "migrants". RÉSULTATS: Vingt-quatre études ont été incluses dans la revue et la méta-analyse, comprenant 12.386 personnes dépistées. Onze études (7.020 patients) ont évalué la présence d'une infection à S. stercoralis uniquement en examinant les larves dans les selles, montrant une prévalence globale de 1% (IC95%: 1-1%). Treize études (5.366 patients) ont utilisé un test sérologique, montrant une prévalence globale de 14% (IC95%: 11-17%). La séroprévalence de la strongyloïdose était de 20% (IC95%: 15-24%) chez les migrants d'Afrique subsaharienne, 14% (IC95%: 10-18%) chez ceux d'Amérique latine et 8% (IC95%: 5-11%) chez ceux d'Afrique du Nord. CONCLUSIONS: Les migrants en provenance de zones d'endémie pour la strongyloïdose vivant en Espagne avaient une prévalence élevée d'infection à S. stercoralis, en particulier ceux d'Afrique subsaharienne et d'Amérique latine. Cette population devrait être dépistée en utilisant la sérologie comme le test le plus sensible pour l' infection à S. stercoralis. Cela pourrait être facilement mis en œuvre au niveau des soins primaires.

Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression.

BACKGROUND: Tumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported. METHODOLOGY: We performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included. PRINCIPAL FINDINGS: Forty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers. CONCLUSIONS: This data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

Acute spinal implant infection treated with debridement: does extended antibiotic treatment improve the prognosis?

The study aims to determine whether 8 weeks of antibiotics is non-inferior to 12 weeks in patients with acute deep spinal implant infection (SII). In the retrospective study of all SII cases (2009-2016), patients aged ≥ 15 years with microbiologically confirmed SII treated with debridement and implant retention were included. Whenever possible, tailored antibiotic treatment was used: rifampin/linezolid in gram-positive and quinolones in gram-negative infection. Patients were divided into short treatment course (8 weeks, ST group) and extended treatment (12 weeks, ET group). Primary outcome measure was percentage of cures at 1-year follow-up. One-hundred-twenty-four patients considered, 48 excluded based on the above criteria, leaving 76 patients, 28 ST and 48 ET. There were no differences in patient age, comorbidities, underlying pathologies, infection location, or surgery characteristics between groups. Surgery-to-debridement time was similar (18.5-day ST vs. 19-day ET; P = 0.96). Sixteen SII cases (21.1%) occurred with bloodstream infection. Pathogens found were Enterobacteriaceae (35, 46.1%), Staphylococcus aureus (29, 38.2%), coagulase-negative staphylococci (12, 15.8%), Pseudomonas aeruginosa (12, 15.8%), and Enterococcus faecalis (7, 9.2%). Twenty seven (35.5%) had polymicrobial infection. E. faecalis was more frequent in the ST group (7, 25% vs. 0; P < 0.001), and P. aeruginosa in ET (1, 3.6% vs. 11, 22.9%; P = 0.05). Five patients died of causes unrelated to SII. At 1-year follow-up, cure rates (21/26 ST, 80.8% vs. 39/45 ET, 86.7%; P = 0.52) and recurrences (2/26, 7.7% vs. 2/45, 4.4%; P = 0.62) were similar. Eight-week antimicrobial courses were not inferior to 12 weeks in patients with acute deep SII treated with prompt debridement, proper wound healing, and optimized antibiotics.