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Abstract 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.

BackgroundHypereosinophilic syndrome can produce cardiac involvement and endomyocardial fibrosis, which have a poor prognosis. However, there is limited information regarding cardiac involvement among migrants from Latin America with eosinophilia related to helminthiasis.MethodsWe conducted a pilot observational study where an echocardiography was performed on migrants from Latin America with both eosinophilia (>450 cells/μL) and a diagnosis of helminth infection, and on migrants from Latin America without eosinophilia or helminth infection. Microbiological techniques included a stool microscopic examination using the Ritchie's formalin-ether technique, and a specific serology to detect Strongyloides stercoralis antibodies.Results37 participants were included, 20 with eosinophilia and 17 without eosinophilia. Twenty (54.1%) were men with a mean age of 41.3 (SD 14.3) years. Helminthic infections diagnosed in the group with eosinophilia were: 17 cases of S. stercoralis infection, 1 case of hookworm infection, and 2 cases of S. stercoralis and hookworm coinfection. Among participants with eosinophilia, echocardiographic findings revealed a greater right ventricle thickness (p = 0.001) and left atrial area and volume index (p = 0.003 and p = 0.004, respectively), while showing a lower left atrial strain (p = 0.006) and E-wave deceleration time (p = 0.008). An increase was shown in both posterior and anterior mitral leaflet thickness (p = 0.0014 and p = 0.004, respectively) when compared with participants without eosinophilia.ConclusionsMigrants from Latin America with eosinophilia related to helminthic infections might present incipient echocardiographic alterations suggestive of early diastolic dysfunction, that could be related to eosinophilia-induced changes in the endomyocardium.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

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.

Abstract Hyponatremia on admission has been related to worse outcomes in patients with COVID-19 infection. However, little is known about the frequency and the associated risk factors of hyponatremia after COVID-19 discharge. We performed an observational 24-month follow-up study of patients admitted during the first COVID-19 wave. Kaplan–Meier curves and Cox proportional hazard models were used to assess the main variables in predicting hyponatremia on follow-up (HYPO-FU). A total of 161 out of 683 (24.4%) developed HYPO-FU. The group with HYPO-FU comprised of more men [(62.3%) vs. (49.2%); p

Background: Imported strongyloidiasis in non-endemic countries has increasingly been diagnosed. The aim of the present study is to describe the main epidemiological and clinical characteristics of patients with imported strongyloidiasis attended in a referral International Health Unit and to detect trend changes over a 12-year period. Methods: This is an observational retrospective study including all imported strongyloidiasis cases seen at the International Health Unit Vall d’Hebron-Drassanes (Barcelona, Spain) from January 2009 to December 2020. Epidemiological and clinical characteristics from included patients were collected. Results: Overall, 865 cases of imported strongyloidiasis were diagnosed, of whom 472 (54.6 %) were men and mean age was 38.7 (SD 13.4) years. Most cases were diagnosed in migrants (830, 96 %). The distribution of the geographic origin was: Latin America (561, 67.6 %), Sub-Saharan Africa (148, 17.8 %), Asia (113, 13.6 %), North Africa (5, 0.6 %), Eastern Europe (2, 0.2 %), and North America (1, 0.1 %). The main reasons for consultation at the Unit were screening of health status (371, 42.9 %), laboratory test alteration (367, 42.4 %), gastrointestinal symptoms (56, 6.5 %), cutaneous symptoms (26, 3 %), and other clinical symptoms (45, 5.2 %). An increase in the number of cases was observed in the last years of the study period. Conclusions: Imported strongyloidiasis has increasingly been diagnosed in our referral unit, mostly due to screening strategies implementation. Most of the patients were young migrants coming from Latin America, with no symptoms at the time of diagnosis. The optimization of screening strategies will increase the detection and treatment of cases, reducing potential complications.

Introduction: Patients with pulmonary tuberculosis (PTB) disease and positive sputum cultures are the main source of infection. Culture conversion time is inconsistent and defining the length of respiratory isolation is challenging. The objective of this study is to develop a score to predict the length of isolation period. Methods: A retrospective study was carried out to evaluated risk factors associated with persistent positive sputum cultures after 4 weeks of treatment in 229 patients with PTB. A multivariable logistic regression model was used to determinate predictors for positive culture and a scoring system was created based on the coefficients of the final model. Results: Sputum culture was persistently positive in 40.6%. Fever at consultation (1.87, 95% CI:1.02–3.41), smoking (2.44, 95% CI:1.36–4.37), >2 affected lung lobes (1.95, 95% CI:1.08–3.54), and neutrophil-to-lymphocyte ratio > 3.5 (2.22, 95% CI:1.24–3.99), were significantly associated with delayed culture conversion. Therefore, we assembled a severity score that achieved an area under the curve of 0.71 (95% CI:0.64–0.78). Conclusions: In patients with smear positive PTB, a score with clinical, radiological and analytical parameters can be used as a supplemental tool to assist clinical decisions in isolation period.

Abstract Background SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients. Methods Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome. Results We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. Conclusions Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications.

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.

Currently available drugs against Trypanosoma cruzi infection, which causes 12000 deaths annually, have limitations in their efficacy, safety and tolerability. The evaluation of therapeutic responses to available and new compounds is based on parasite detection in the bloodstream but remains challenging because a substantial proportion of infected individuals have undetectable parasitemia even when using diagnostic tools with the highest accuracy. We characterize parasite dynamics which might impact drug efficacy assessments in chronic Chagas by analyzing pre- and post-treatment quantitative-PCR data obtained from blood samples collected regularly over a year. We show that parasitemia remains at a steady-state independently of the diagnostic sensitivity. This steady-state can be probabilistically quantified and robustly predicted at an individual level. Furthermore, individuals can be assigned to categories with distinct parasitological status, allowing a more detailed evaluation of the efficacy outcomes and adjustment for potential biases. Our analysis improves understanding of parasite dynamics and provides a novel background for optimizing future drug efficacy trials in Chagas disease. Trial Registration: original trial registered with ClinicalTrials.gov, number NCT01489228.

Objectives: The majority of available scores to assess mortality risk of coronavirus disease 2019 (COVID-19) patients in the emergency department have high risk of bias. Therefore, this cohort aimed to develop and validate a score at hospital admission for predicting in-hospital mortality in COVID-19 patients and to compare this score with other existing ones. Methods: Consecutive patients (≥ 18 years) with confirmed COVID-19 admitted to the participating hospitals were included. Logistic regression analysis was performed to develop a prediction model for in-hospital mortality, based on the 3978 patients admitted between March–July, 2020. The model was validated in the 1054 patients admitted during August–September, as well as in an external cohort of 474 Spanish patients. Results: Median (25–75th percentile) age of the model-derivation cohort was 60 (48–72) years, and in-hospital mortality was 20.3%. The validation cohorts had similar age distribution and in-hospital mortality. Seven significant variables were included in the risk score: age, blood urea nitrogen, number of comorbidities, C-reactive protein, SpO2/FiO2 ratio, platelet count, and heart rate. The model had high discriminatory value (AUROC 0.844, 95% CI 0.829–0.859), which was confirmed in the Brazilian (0.859 [95% CI 0.833–0.885]) and Spanish (0.894 [95% CI 0.870–0.919]) validation cohorts, and displayed better discrimination ability than other existing scores. It is implemented in a freely available online risk calculator (https://abc2sph.com/). Conclusions: An easy-to-use rapid scoring system based on characteristics of COVID-19 patients commonly available at hospital presentation was designed and validated for early stratification of in-hospital mortality risk of patients with COVID-19.

Background: The impact of COVID-19 on the diagnosis and management of tuberculosis (TB) patients is unknown. Methods: Participating centres completed a structured web-based survey regarding changes to TB patient management during the COVID-19 pandemic. The study also included data from participating centres on patients aged ≥18 diagnosed with TB in 2 periods: March 15 to June 30, 2020 and March 15 to June 30, 2019. Clinical variables and information about patient household contacts were retrospectively collected. Results: A total of 7 (70%) TB units reported changes in their usual TB team operations. Across both periods of study, 169 patients were diagnosed with active TB (90 in 2019, 79 in 2020). Patients diagnosed in 2020 showed more frequent bilateral lesions in chest X-ray than patients diagnosed in 2019 (P = 0.004). There was a higher percentage of latent TB infection and active TB among children in households of patients diagnosed in 2020, compared with 2019 (P = 0.001). Conclusions: The COVID-19 pandemic has caused substantial changes in TB care. TB patients diagnosed during the COVID-19 pandemic showed more extended pulmonary forms. The increase in latent TB infection and active TB in children of patient households could reflect increased household transmission due to anti-COVID-19 measures.

The screening and treatment of latent tuberculosis infection (LTBI) in countries with a low incidence of TB is a key strategy for the elimination of tuberculosis (TB). However, treatment can result in adverse events (AEs) and have poor adherence. This study aimed to describe treatment outcomes and AEs for LTBI patients at two departments in Vall d’Hebron University Hospital in Barcelona, Spain. A retrospective study was conducted on all persons treated for LTBI between January 2018 and December 2020. Variables collected included demographics, the reason for LTBI screening and treatment initiation, AEs related to treatment, and treatment outcome. Out of 261 persons who initiated LTBI treatment, 145 (55.6%) were men, with a median age of 42.1 years. The indications for LTBI screening were household contact of a TB case in 96 (36.8%) persons, immunosuppressive treatment in 84 (32.2%), and recently arrived migrants from a country with high TB incidence in 81 (31.0%). Sixty-three (24.1%) persons presented at least one AE during treatment, and seven (2.7%) required definitive discontinuation of treatment. In the multivariate analysis, AE development was more frequent in those who started LTBI treatment due to immunosuppression. Overall, 226 (86.6%) completed treatment successfully. We concluded that LTBI screening and treatment groups had different risks for adverse events and treatment outcomes. Persons receiving immunosuppressive treatment were at higher risk of developing AEs, and recently arrived immigrants from countries with a high incidence of TB had greater LTFU. A person-centered adherence and AE management plan is recommended.

BackgroundTwo years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted for clinical management and in most algorithms the contribution of laboratory variables is limited.ObjectivesTo measure the predictive performance of currently used clinical laboratory tests alone or combined with clinical variables and explore the predictive power of immunological tests adequate for clinical laboratories. Methods: Data from 2,600 COVID-19 patients of the first wave of the pandemic in the Barcelona area (exploratory cohort of 1,579, validation cohorts of 598 and 423 patients) including clinical parameters and laboratory tests were retrospectively collected. 28-day survival and maximal severity were the main outcomes considered in the multiparametric classical and machine learning statistical analysis. A pilot study was conducted in two subgroups (n=74 and n=41) measuring 17 cytokines and 27 lymphocyte phenotypes respectively.Findings1) Despite a strong association of clinical and laboratory variables with the outcomes in classical pairwise analysis, the contribution of laboratory tests to the combined prediction power was limited by redundancy. Laboratory variables reflected only two types of processes: inflammation and organ damage but none reflected the immune response, one major determinant of prognosis. 2) Eight of the thirty variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the combined statistical predictive power. 3) The interpretation of clinical and laboratory variables was moderately improved by grouping them in two categories i.e., inflammation related biomarkers and organ damage related biomarkers; Age and organ damage-related biomarker tests were the best predictors of survival, and inflammatory-related ones were the best predictors of severity. 4) The pilot study identified immunological tests (CXCL10, IL-6, IL-1RA and CCL2), that performed better than most currently used laboratory tests.ConclusionsLaboratory tests for clinical management of COVID 19 patients are valuable but limited predictors due to redundancy; this limitation could be overcome by adding immunological tests with independent predictive power. Understanding the limitations of tests in use would improve their interpretation and simplify clinical management but a systematic search for better immunological biomarkers is urgent and feasible.

Chronic chagasic cardiomyopathy (CCC) is the most important complication of patients with Chagas disease (CD). The role of persistent detection of DNA in peripheral blood and its association to CCC is unknown. We performed a systematic review up to July 2021, including studies that reported ratios of CCC and PCR positivity among non-treated adult patients. We identified 749 records and selected 12 for inclusion corresponding to 1,686 patients. Eight studies were performed in endemic countries and 4 in non-endemic countries. Only two studies showed an association between CCC and Trypanosoma cruzi parasitemia by means of PCR detection. Six studies reported greater positive PCR ratios among patients with CCC than in the patients with indeterminate chagas disease (ICD) with no statistical significance. A significant risk of bias has been detected among most of the studies. Therefore, while we performed a meta-analysis, wide inter-study heterogeneity impeded its interpretation.ConclusionsWith the available information, we could not establish a correlation between PCR-detectable parasitemia and CCC.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216072, identifier: CRD42020216072.

(1) Background: Angola is among the high-burden countries with malaria cases globally. After 2013, we suspected an increase in the number of malaria cases in Cubal (Angola), previously in decline. Our objective was to evaluate the incidence rate in Cubal, overall and by neighborhood, for 2014, 2015, and 2016. (2) Methods: A retrospective, observational study was performed in Cubal (Angola) from January 2014 to December 2016, including all patients with a microbiologically confirmed diagnosis, treated at Cubal’s Hospitals for this period of time. The principal variables calculated were the incidence rates of 2014, 2015, and 2016 in Cubal (overall and by neighborhood). (3) Results: There were 3249 malaria cases. The incidence rates were 2.27, 10.73, and 12.40 cases per 1000 inhabitants in 2014, 2015, and 2016, respectively. In the neighborhood, Hamavoko-Kasseke, there was a 10.73-fold increase in incidence during this period. Additionally, Hamavoko-Kasseke presents an anomalous distribution of malaria cases. (4) Conclusions: We observed an increase in the incidence of malaria in Cubal during the three-year study period. The case distribution was highly heterogeneous with hyperendemic areas, and we found a chronobiological association between the construction of a civil engineering project. This information could be useful for deciding which malaria control strategies must be implemented in this area.

ABSTRACT We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB2−TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD8+ T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-γ) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB2−TB1 value >0.6 IU·ml−1 was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2>TB1 result in the contact, IMID, and ASPFA groups, respectively (P = 0.591). The adjusted odds ratios (aORs) for an association between a TB2−TB1 result of >0.6 IU·ml−1 and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 15.4%, and 17.7% with close, frequent, and sporadic contact had a TB2>TB1 result (P = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB2−TB1 difference of >0.6 IU·ml−1 was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection. IMPORTANCE Contact tuberculosis tracing is essential to identify recently infected people, who therefore merit preventive treatment. However, there are no diagnostic tests that can determine whether the infection is a result of a recent exposure or not. It has been suggested that by using the QuantiFERON-TB gold plus, an interferon gamma (IFN-γ) release assay, a difference in IFN-γ production between the two antigen tubes (TB2 minus TB1) of >0.6 IU·ml−1 could serve as a proxy marker for recent infection. In this large multinational study, infected individuals could not be classified according to the risk of recent exposure based on differences in IFN-γ in TB1 and TB2 tubes that were higher than 0.6 IU·ml−1. QuantiFERON-TB gold plus is not able to distinguish between recent and remotely acquired tuberculosis infection, and it should not be used for that purpose in contact tuberculosis tracing.

BackgroundLeishmaniasis is a neglected disease caused by different species of the protozoa Leishmania spp. Cutaneous lesions are the most common clinical manifestation. This disease is prevalent in tropical and subtropical areas, including the Mediterranean basin. In Spain, Leishmania (L.) infantum is the only endemic species, but imported cases are often diagnosed. Different classical parasitological methods can be performed for cutaneous leishmaniasis (CL) diagnosis; but currently molecular techniques serve as a relevant tool for the detection and characterization of Leishmania parasites. We aimed to evaluate clinical and epidemiological characteristics of CL diagnosed patients by real-time PCR in a tertiary hospital over a six-year period.Methodology/principal findingsClinical, epidemiological and microbiological data were retrospectively collected and analyzed. In our study, CL was confirmed in 59 (31.4%) out of 188 patients by real-time PCR, showing an increase over recent years: 11 cases of CL between 2014 and 2016 and 48 between 2017 and 2019. Real-time PCR was performed on skin swabs and/or biopsies samples, with a positivity of 38.5% and 26.5%, respectively. Results were 100% concordant when biopsy and skin swab were performed simultaneously. L. (L.) infantum was the most frequent species detected (50%), followed by L. (L.) major (45%) and Viannia subgenus (5%), which were detected only in imported cases. L. (L.) major was almost entirely detected in travelers/migrants from Morocco. Multiple and atypical skin lesions were more common in imported cases than in autochthonous cases (44.4% vs. 21.8%).Conclusions/significanceAn increase in both autochthonous and imported CL cases has been observed in past years in our hospital. Molecular techniques assist in improving CL diagnosis and characterization of the Leishmania species, mainly in imported cases.

Abstract Background Chagas disease is a protozoan infection caused by Trypanosoma cruzi. The disease has a chronic course in which 20–30% of the patients would develop progressive damage to the cardiovascular system and the gastrointestinal tube. We are still unable to predict who will develop end-organ damage but there are some acquired and genetic risk factors already known. Results We reviewed data from 833 patients with serologically confirmed Chagas disease in this retrospective study. Patients were classified as siblings or non-siblings (controls) and the results of pre-treatment blood PCR assay, end-organ damage (cardiac and/or gastrointestinal), and the presence of delayed type hypersensitivity (DTH) skin involvement in patients treated with benznidazole were analyzed. Siblings were grouped by family and we randomly generated groups of 2 or 3 persons with the remaining controls. We classified the results of each variable as concordant or discordant and compared the concordance in these results among the sibling groups with that among control groups. We identified 71 groups of siblings and randomly generated 299 groups of non-related patients. Pre-treatment blood PCR concordance was significantly higher (19%) among siblings compared to controls (P = 0.02), probably due to a higher frequency in pre-treatment positive results. No other statistically significant differences were found. Conclusions A significant difference was found in the concordance of pre-treatment blood PCR for T. cruzi among siblings compared to non-related controls.

BackgroundChagas disease is a public health problem not only in Latin America, but also in other regions, including Spain, due to migration movements. Conventional serological diagnosis requires an invasive sample (plasma or serum) and a well-equipped laboratory. To circumvent those limitations, blood samples dried on filter paper (DBS) or Rapid Diagnostic Test (RDT) could be a practical alternative to reference protocol for serological screening in epidemiological studies. We evaluated the usefulness of dried blood sampling and a rapid diagnostic test (Trypanosoma Detect™) for the detection of antibodies against T. cruzi for their use in community-based screening.Methodology/Principal FindingsA total of 162 stored paired whole-blood and serum samples from Latin American migrants and 25 negative-control blood samples were included. Diagnosis of chronic Chagas disease was performed in serum according to WHO algorithms. Blood samples were retrospectively collected as dried spots and then analyzed using two different serological techniques, enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay (E-CLIA). Whole-blood samples were also used to evaluate a rapid diagnostic test based on immunochromatography. A better correlation with conventional serum was observed in dried blood elutes using E-CLIA than ELISA (97% vs. 77% sensitivity, respectively). Both assays reported 100% specificity. The median cut-off index values of E-CLIA for dried blood were significantly lower than those for serum (138.1 vs. 243.3, P

BackgroundChagas disease (CD) is regarded as a possible risk for travellers to endemic areas of continental Latin America (LA). The aim of the study is to determine the risk of Trypanosoma cruzi (TC) infection among travellers to CD endemic areas and to identify risk factors for acquiring TC infection.Methods/principal findingWe designed a multicenter cross-sectional study among travellers in Spain (Badalona, Barcelona and Madrid). All available adults with laboratory confirmed proof of absence of TC infection from January 2012 to December 2015 were contacted. Participants referring a trip to LA after the negative TC screening were offered to participate. We performed a standardized questionnaire of travel related factors and measurement of TC antibodies in serum. A total of 971 participants with baseline negative TC serology were selected from the microbiology records. After excluding participants not meeting inclusion criteria, eighty participants were selected. Sixty three (78.8%) were female, and the median age was 38 (IQR 34-47) years. The reason to travel was visiting friends and relatives in 98.8% of the participants. The median duration of travel was 40 (IQR 30-60) days, with 4911 participants-day of exposure. Seventy seven cases (96.25%) participants had two negative TC serology tests after the travel, two cases (2.5%) had discordant serology results (considered false positive results) and one case was infected before travelling to LA. According to our data, the upper limit of the 95% confidence interval of the incidence rate of TC acquisition in travellers is 0.8 per 1000 participant-days.Conclusions/significanceAmong 79 non-CD travellers to TC endemic areas, we found no cases of newly acquired TC infection. The incidence rate of TC acquisition in travellers to endemic countries is less than or equal to 0.8 per 1000 traveller-days.

Human T-cell lymphotropic virus type 1 and 2 (HTLV-1/2) screening is not mandatory in Spanish blood banks. In Catalonia, selective screening was introduced in 2008, followed by universal screening in 2011. We present herein a 10-year experience of HTLV testing in blood donors. HTLV-1/2 selective screening was performed using Ortho-Clinical Diagnostics HTLV-I/HTLV-II Ab-Capture ELISA between February 2008 and May 2009, then Abbott Prism HTLV-I/ HTLV-II assay until December 2010. Abbott Architect rHTLV-I/II assay was then used for HTLV-1/2 universal screening in pooled samples. INNO-LIA HTLV I/II Score (Fujirebio) and in-house HTLV-1/2 proviral DNA real-time PCR were used in reactive samples. Follow-up was offered to confirm HTLV-1/2 donors in Vall d’Hebron Hospital. Between 2008 and 2017, 51 blood donors were confirmed HTLV positive (46 HTLV-1, 4 HTLV-2 and 1 HTLV) out of 2,114,891 blood donations (1 in 41,468). Sixty-nine percent were female, median age was 40 years and most were born in Latin America (69%), followed by Europe (25%), Africa (4%) and Asia (2%). Screening of relatives and partners identified 12 additional HTLV-1 cases. Lookback studies did not show any HTLV-1/2 transmission. HTLV infections found in blood donors mirror epidemiological changes in the population of Spain. Consequently, HTLV should be considered a potential risk for recipients and calls for the design of optimal strategies to ensure transfusion safety.

Microfluidic paper-based analytical devices (μPADs) have been extensively proposed as ideal tools for point-of-care (POC) testing with minimal user training and technical requirements. However, most μPADs use dried bioreagents, which complicate production, reduce device reproducibility and stability, and require transport and storage under temperature and humidity-controlled conditions. In this work, we propose a μPAD produced using an affordable craft-cutter and stored at room temperature, which is used to partially automate a single-step colorimetric magneto-immunoassay. As a proof-of-concept, the μPAD has been applied to the quantitative detection of Plasmodium falciparum lactate dehydrogenase (Pf-LDH), a biomarker of malaria infection. In this system, detection is based on a single-step magneto-immunoassay that consists of a single 5-min incubation of the lysed blood sample with immuno-modified magnetic beads (MB), detection antibody, and an enzymatic signal amplifier (Poly-HRP). This mixture is then transferred to a single-piece paper device where, after on-chip MB magnetic concentration and washing, signal generation is achieved by adding a chromogenic enzyme substrate. The colorimetric readout is achieved by the naked eye or using a smartphone camera and free software for image analysis. This μPAD afforded quantitative Pf-LDH detection in −1 when the result was interpreted by the naked eye and 1.4 ng mL−1 when analysed using the smartphone imaging system. Moreover, the study of a battery of clinical samples revealed concentrations of Pf-LDH that correlated with those provided by the reference ELISA and with better sensitivity than a commercial rapid diagnostic test (RDT). These results demonstrate that magneto-immunoassays can be partly automated by employing a μPAD, achieving a level of handling that approaches the requirements of POC testing.

The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.

Objective: Blastocystis sp. is one of the most frequently observed intestinal parasites in humans. It is suggested that sensitivity of classical parasitological tests for the Blastocystis sp. diagnosis increases when increasing the number of investigated samples, although there is a lack of information. The aim of the study is to evaluate the sensitivity of classical parasitological tests for the Blastocystis sp. diagnosis depending on the number of investigated samples and to determine risk factors associated to high parasite burden. Methods: Retrospective study where patients in whom three consecutive stool samples were examined for parasitic diagnosis through microscopic examination at Vall d'Hebron University Hospital (Barcelona, Spain) from January to April 2019 were included. To determine risk factors associated to high parasite burden, a case-control study was performed including patients with at least one positive stool sample for Blastocystis sp.: cases were those patients with only one or two positive stool samples, and controls were those with all three stool positive samples). Clinical records were reviewed from included patients to collect clinical and demographic information. Results: In 2771 patients three consecutive stool samples were examined for parasitic diagnosis, with an overall prevalence of Blastocystis sp. detection of 23.3%. The proportions of positive cases depending on the number of investigated samples were: 22.3% when taking into account the first sample, 22.9% when taking into account the first and second samples, and 23.3% when taking into account the three samples, with no statistically significant differences among them. For the case-control study we finally included 63 cases and 133 controls. No differences were found regarding clinical and demographic characteristics among groups. Conclusion: Prevalence of Blastocystis sp. infection was high in our study (23.3%). The sensitivity of classical parasitological methods for Blastocystis sp. diagnosis did not increase when increasing the number of investigated samples, and no risk factors associated to high parasite burden were identified.

Background: The confirmatory diagnosis of pleural tuberculosis (pTB) remains challenging. The aim of this study was to describe the clinical and epidemiological characteristics of pTB patients and assess the yield of different diagnostic procedures in a low burden country with a high rate of immigrant population. Methods: All adult patients with pTB between 2007 and 2014 were studied retrospectively. Results: One hundred and three out of 843 patients with tuberculosis had pTB. Fifty-three (54.1%) were male, and the median age was 45 years (range 18–87 years). Fifty-two (50.49%) patients were immigrants. A confirmed diagnosis was reached in 16 patients (15.5%) by microbiological studies of pleural effusion. Lung involvement was demonstrated by sputum smear microscopy in 13/49 (26.5%), sputum GeneXpert MTB/RIF test in 13/20 (65%), and sputum culture in 16/37 (43.2%). High-resolution computed tomography (CT) showed lung involvement in 47.7% of the patients. The cure rate was 91.3% at the 1-year follow-up. Three patients died, all of them within the first month after diagnosis. Conclusions: The detection of lung involvement increased by two-fold when lung CT was used; this correlated with the likelihood of finding a positive microbiological result on sputum sample testing. Pleural microbiological studies had a low diagnostic yield, and sputum could have a complementary role. Keywords: Pleural tuberculosis, Immigrant population, Tuberculosis diagnostic tools

Abstract Background Current available treatments (benznidazole and nifurtimox) for Chagas disease (CD) show limited efficacy in chronic phase and frequent undesirable effects. Ergosterol synthesis inhibitors (ESI) had been considered as promising drugs for CD treatment and despite its recent poor results in several clinical trials, different strategies have been proposed to optimize its role in this infection. Case presentation We present a case of chronic Chagas disease in patient diagnosed with HIV who received treatment for histoplasmosis with itraconazol during twelve months. Even though T. cruzi rt-PCR was persistently negative during treatment, when itraconazol was stopped she presented with a positive blood rt-PCR. Conclusion Several studies using different ESI had been published for CD treatment. Either in vitro or in vivo assays demonstrated activity against T. cruzi of the different triazole derivatives so different clinical trials had been carried out to evaluate its efficacy and safety. Despite contradictory evidence in the animal model, longer treatments along with other treatment strategies previously proposed suggests that ESI failure rates in positive peripheral blood rt-PCR are higher than that obtained with the current treatments of choice.

BACKGROUND:Antitrypanosomal treatment with Benznidazole (BZ) or Nifurtimox may be recommended for patients with chronic Chagas disease (CD) to reduce the onset or progression of symptoms. However, such treatment has limited efficacy and high level of toxic effects. In addition, the current cure biomarker (serology conversion) precludes any treatment assessment unless a prolonged follow-up is arranged. PCR is thus the most useful, alternative surrogate marker for evaluating responses to treatment. The aim of this study is to describe the usefulness of real-time PCR in monitoring BZ treatment within a large cohort of chronic CD cases in Barcelona. METHODOLOGY/PRINCIPAL FINDINGS:A total of 370 chronic CD patients were monitored with real-time PCR post-BZ treatment. The median follow-up was 4 years (IQR 2.2-5.3y), with a median of 3 clinical visits (IQR 2-4). Only 8 patients (2.2%) presented with at least one incident of positive real-time PCR after treatment and were therefore considered as treatment failure. Four of those failure patients had completed full course treatment, whereas the remaining cases had defaulted with a statistical difference between both groups (p = 0.02). Half of the failure patients had undergone less than 4 years of follow-up monitoring all presented with parasitemia before treatment. CONCLUSIONS/SIGNIFICANCE:BZ treatment failure was highly infrequent in our cohort. BZ discontinuation was a risk factor for positive real-time PCR results during clinical follow-up. Regular testing with real-time PCR during follow-up allows for early detection of treatment failure in patients with chronic CD.

BackgroundTumor 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.MethodologyWe 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 findingsForty-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.ConclusionsThis 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.

BackgroundImported strongyloidiasis is increasingly being diagnosed in non-endemic areas. The aim of this study was to describe the epidemiological, clinical and microbiological characteristics of patients with imported strongyloidiasis in Spain.MethodologyThis is an observational retrospective study that included all patients diagnosed of strongyloidiasis registered in the +REDIVI Collaborative Network from 2009 to 2017. Demographic, epidemiological and clinical information was collected from the +REDIVI database, and extra information regarding microbiological techniques, treatment and follow-up was requested to participant centers.FindingsOverall, 1245 cases were included. Most of them were immigrants (66.9%), and South America was the most frequent area of origin. Detection of larvae in stool samples was observed in 21.9% of the patients, and serological tests allowed making the diagnosis in the rest of the cases. Eosinophilia was present in 82.2% of cases. Treatment with ivermectin (compared with albendazole) was the most strongly associated factor to achieve the cure (OR 2.34).ConclusionsGiven the long latency of the infection and the risk of developing a severe presentation, screening of S. stercoralis infection should be mandatory in patients coming from or had traveling to endemic areas, especially in those with immunosuppressant conditions.

Background: There is no consensus for the best treatment of complex cutaneous leishmaniasis (CL). We aimed to describe a cohort of CL, focusing on liposomal amphotericin B (L-AmB) treatment outcome. Methods: We performed a retrospective study in Vall d’Hebron University Hospital (Barcelona, Spain). All patients with parasitologically proven CL diagnosed from 2012 to 2018 were included. Results: The analysis included 41 patients with CL. The median age was 39 years (IQR 12- 66); 12 (29%) were children, and 29 (71%) were men. Regarding treatment, 24 (59%) received local treatment, whereas 17 (41%) had complex CL and were offered intravenous systemic treatment. Sixteen patients received L-AmB; eight (50%) had adverse events, and three (19%) discontinued treatment for safety reasons. All cases were considered cured within the first year post-treatment. Conclusions: L-AmB for complex CL showed no treatment failures, offering an alternative treatment option for patients with complex CL. Clinicians should pay close attention to the potential adverse events of L-AmB and adopt an active drug safety surveillance scheme to rapidly detect reversible side effects.

Background: The aim of the present study is to describe the occurrence of Blastocystis sp. detection among asymptomatic subjects and patients with irritable bowel syndrome in order to evaluate the potential association between irritable bowel syndrome and the parasitic infection. Methods: Cross-sectional study where adult patients with irritable bowel syndrome diagnosed according to Rome IV criteria were included. A control group was formed by asymptomatic subjects older than 18 years. Exclusion criteria were: immunosuppressive condition or having received any drug with demonstrated activity against Blastocystis sp. within the last 6 months before study inclusion. Epidemiological and clinical information was collected from all included participants. Two stool samples were obtained from all participants: one sample for microscopic examination and one sample for Blastocystis sp. PCR detection. Blastocystis sp. infection was defined by the positivity of any of the diagnostic techniques. Results: Seventy-two participants were included (36 asymptomatic subjects and 36 patients with irritable bowel syndrome). Thirty-five (48.6%) were men, and median age of participants was 34 (IQR 29–49) years. The overall rate of Blastocystis sp. carriage was 27.8% (20/72). The prevalence assessed through microscopic examination was 22.2% (16/72), while the prevalence measured by PCR was 15.3% (11/72). When comparing the presence of Blastocystis sp. between asymptomatic subjects and IBS patients, we did not find any statistically significant difference (36.1% vs. 19.4% respectively, p = 0.114). Conclusions: regarding the occurrence of Blastocystis sp., no differences were found between asymptomatic participants and patients with irritable bowel disease irrespective of the diagnostic technique performed.

BACKGROUND:Strongyloides stercoralis infection, a neglected tropical disease, is widely distributed. Autochthonous cases have been described in Spain, probably infected long time ago. In recent years the number of diagnosed cases has increased due to the growing number of immigrants, travelers and refugees, but endemically acquired cases in Spain remains undetermined. METHODOLOGY:We systematically searched the literature for references on endemic strongyloidiasis cases in Spain. The articles were required to describe Strongyloides stercoralis infection in at least one Spanish-born person without a history of travel to endemic areas and be published before 31st May 2018. Epidemiological data from patients was collected and described individually as well as risk factors to acquisition of the infection, diagnostic technique that lead to the diagnosis, presence of eosinophilia and clinical symptoms at diagnosis. FINDINGS:Thirty-six studies were included, describing a total of 1083 patients with an average age of 68.3 years diagnosed with endemic strongyloidiasis in Spain. The vast majority of the cases were described in the province of Valencia (n = 1049). Two hundred and eight of the 251 (82.9%) patients in whom gender was reported were male, and most of them had current or past dedication to agriculture. Seventy percent had some kind of comorbidity. A decreasing trend in the diagnosed cases per year is observed from the end of last decade. However, there are still nefigw diagnoses of autochthonous cases of strongyloidiasis in Spain every year. CONCLUSIONS:With the data provided by this review it is likely that in Spain strongyloidiasis might have been underestimated. It is highly probable that the infection remains undiagnosed in many cases due to low clinical suspicion among Spanish population without recent travel history in which the contagion probably took place decades ago.

BackgroundThe aim of our study is to describe the FDG-PET/CT findings in patients with tuberculosis and to correlate them with the patient's prognosis.MethodsWe retrospectively collected data from patients with tuberculosis, who had an FDG-PET/CT performed prior to treatment initiation from 2010 to 2015.ResultsForty-seven out of 504 patients with active tuberculosis diagnosis (9.33%) underwent an FDG-PET/CT. The reasons for performing the FDG-PET/CT were: characterization of a pulmonary nodule (24; 51.1%), study of fever of unknown origin (12; 25.5%), study of lymph node enlargement (5; 10.6%) and others (6; 12.8%). Median age was 64 (IQR 50-74) years and 31 (66%) patients were male. Twenty-six (55.3%) patients had an immunosuppressant condition. According to the FDG-PET/CT, 48.6% of the patients had more than 1 organ affected and 46.8% had lymph node involvement. Median SUVmax of the main lesion was 5 (IQR 0.28-11.85). We found an association between the FDG accumulation and the size of the main lesion with a correlation coefficient of 0.54 (pConclusionsIn our cohort, almost half of the patients had more than 1 organ affected and 46.8% of them had lymph node involvement. FDG uptake was associated with the size of the main lesion and seems to be related to the treatment outcome. The extent of its potential to be used as an early predictor of treatment success still needs to be defined.

Endemic mycoses are systemic fungal infections. Histoplasmosis is endemic in all temperate areas of the world; coccidioidomycosis and paracoccidioidomycosis are only present in the American continent. These pathogens are not present in Spain, but in the last years there has been an increase of reported cases due to migration and temporary movements. We obtained from the Spanish hospitals records clinical and demographic data of all hospitalized cases between 1997 and 2014. There were 286 cases of histoplasmosis, 94 of Coccidioidomycosis and 25 of paracoccidioidomycosis. Overall, histoplasmosis was strongly related to HIV infection, as well as with greater morbidity and mortality. For the other mycoses, we did not find any immunosuppressive condition in most of the cases. Although we were not able to obtain data about clinical presentation of all the cases, the most frequently found was pulmonary involvement. We also found a temporal correlation between the Spanish population born in endemic countries and the number of hospitalized cases along this period. This study reflects the importance of imported diseases in non-endemic countries due to migratory movements.

BACKGROUND:Helminth infections are highly prevalent in tropical and subtropical countries, coexisting in Chagas disease endemic areas. Helminth infections in humans may modulate the host immune system, changing the Th1/Th2 polarization. This immunological disturbance could modify the immune response to other infections. The aim of this study is to evaluate the relationship between clinical, microbiological and epidemiological characteristics of Chagas disease patients, with the presence of helminth infection. METHODS:A prospective observational study was conducted at Vall d'Hebron University Hospital (Barcelona, Spain). Inclusion criteria were: age over 18 years, diagnosis of Chagas disease, and not having received specific treatment for Chagas disease previously to the inclusion. The study protocol included Chagas disease assessment (cardiac and digestive evaluation, detection of T. cruzi DNA measured by PCR in peripheral blood), and helminth infection diagnosis (detection of IgG anti-Strongyloides stercoralis by ELISA, microscopic examination of stool samples from three different days, and specific faecal culture for S. stercoralis larvae). RESULTS:Overall, 65 patients were included, median age was 38 years, 75.4% were women and most of them came from Bolivia. Cardiac and digestive involvement was present in 18.5% and 27.7% of patients respectively. T. cruzi PCR was positive in 28 (43.1%) patients. Helminth infection was diagnosed in 12 (18.5%) patients. No differences were observed in clinical and epidemiological characteristics between patients with and without helminth infection. Nevertheless, the proportion of patients with positive T. cruzi PCR was higher among patients with helminth infection compared with patients without helminth infection (75% vs 35.8%, p = 0.021). CONCLUSIONS:We observed a high prevalence of S. stercoralis infection among chronic Chagas disease patients attended in our tropical medicine unit. Strongyloidiasis was associated with significantly higher proportion of positive T. cruzi RT-PCR determined in peripheral blood.