Usefulness of Xpert MTB/RIF and Xpert Ultra to Categorize Risk of Tuberculosis Transmission to Household Contacts.

Background: People with pulmonary tuberculosis (PTB) are contagious, particularly to their household contacts. Their infectivity has been associated with the bacterial load in sputum samples. This study investigated if the bacterial load in sputum samples as quantified by Xpert MTB/RIF and Xpert Ultra is correlated with the extent that latent tuberculosis infection (LTBI) occurred in household contacts of people with PTB. Methods: A retrospective study was performed including people with PTB presenting at Vall d'Hebron University Hospital, Barcelona, between 2011 and 2021. Their infection ratio, representing the proportion of household members found with LTBI in contact tracing investigation, was compared with the quantitative results of Xpert MTB/RIF and Xpert Ultra using ordinal regression analysis. Results: A total of 107 people with PTB were included. Among their 398 household contacts, 126 (31.7%) cases of LTBI and 14 cases with active TB disease (3.5%) were reported. Higher bacterial load in Xpert MTB/RIF and Xpert Ultra baseline sputum was significantly associated with increased infection ratios, providing better estimates than conventional acid-fast bacilli (AFB) smear grading. Conclusions: Xpert MTB/RIF and Xpert Ultra could serve as an alternative to AFB sputum-smear grading in determining contact tracing priorities.

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.

Endomyocardial involvement in asymptomatic Latin American migrants with eosinophilia related to helminth infection: A pilot study.

BACKGROUND: Hypereosinophilic 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. METHODS: We 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. RESULTS: 37 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. CONCLUSIONS: Migrants 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.

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.

[Update on the treatment of tuberculosis]. / Actualización sobre el tratamiento de la tuberculosis.

Tuberculosis (TB) affects more than 10 million people each year. We have contested this burden with a paradoxically slow development of treatments, as compared to other infectious diseases. This review aims to update health care professionals on the last developments for the management of TB. The combination of drugs established more than 40years ago is still adequate to cure most people affected by TB. However, with the generalisation of regimens based on rifampicin and isoniazid for (only) 6months, resistance emerged. Resistant cases needed long treatments based on injectable drugs. Now, after an exciting decade of research, we can treat resistant TB with oral regimens based on bedaquiline, nitroimidazoles, and linezolid for (only) 6months, and we may soon break the 6-month barrier for treatment duration. However, these improvements are not enough to end TB without an engagement of people affected and their communities to achieve adherence to treatment, transmission control, and improve socioeconomic determinants of health.

Tuberculosis contact tracing, Angola.

Objective: To assess the outcomes of a contact-tracing programme to increase the diagnosis of tuberculosis in Cubal, Angola and offer preventive treatment to high-risk groups. Methods: A health centre-based contact-tracing programme was launched in Hospital Nossa Senhora da Paz in March 2015 and we followed the programme until 2022. In that time, staffing and testing varied which we categorized as four periods: medical staff reinforcement, 2015-2017, with a doctor seconded from Vall d'Hebron University Hospital, Spain; routine staff, 2017-2021, with no external medical support; community directly observed treatment (DOT), 2018-2019 with community worker support; and enhanced contact tracing, 2021-2022, with funding that allowed free chest radiographs, molecular and gastric aspirate testing. We assessed differences in contacts seen each month, and testing and treatment offered across the four periods. Findings: Overall, the programme evaluated 1978 contacts from 969 index cases. Participation in the programme was low, although it increased significantly during the community DOT period. Only 16.6% (329/1978) of contacts had a chest radiograph. Microbiological confirmation increased to 72.2% (26/36) after including molecular testing, and 10.1% (200/1978) of contacts received treatment for tuberculosis. Of 457 contacts younger than 5 years, 36 (7.9%) received preventive tuberculosis treatment. Half of the contacts were lost to follow-up before a final decision was taken on treatment. Conclusion: Contact tracing increased the diagnosis of tuberculosis although engagement with the programme was low and loss to follow-up was high. Participation increased during community DOT. Community-based screening should be explored to improve participation and diagnosis.

A longitudinal prospective study of active tuberculosis in a Western Europe setting: insights and findings.

PURPOSE: This study investigates the potential of inflammatory parameters (IP), symptoms, and patient-related outcome measurements as biomarkers of severity and their ability to predict tuberculosis (TB) evolution. METHODS: People with TB were included prospectively in the Stage-TB study conducted at five clinical sites in Barcelona (Spain) between April 2018 and December 2021. Data on demographics, epidemiology, clinical features, microbiology, and Sanit George Respiratory Questionnaire (SGRQ) and Kessler-10 as Health-Related Quality of Life (HRQoL) were collected at three time points during treatment. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil/lymphocyte, and monocyte/lymphocyte ratios (NLR and MLR), complement factors C3, C4, and cH50, clinical and microbiological data, and HRQoL questionnaires were assessed at baseline, 2 months, and 6 months. Their ability to predict sputum culture conversion (SCC) and symptom presence after 2 months of treatment was also analysed. RESULTS: The study included 81 adults and 13 children with TB. The CRP, ESR, NLR, and MLR values, as well as the presence of symptoms, decreased significantly over time in both groups. Higher IP levels at baseline were associated with greater bacillary load and persistent symptoms. Clinical severity at baseline predicted a delayed SCC. Kessler-10 improved during follow-up, but self-reported lung impairment (SGRQ) persisted in all individuals after 6 months. CONCLUSIONS: IP levels may indicate disease severity, and sustained high levels are linked to lower treatment efficacy. Baseline clinical severity is the best predictor of SCC. Implementing health strategies to evaluate lung function and mental health throughout the disease process may be crucial for individuals with TB.

Mycobacterium avium complex pulmonary disease patients with limited treatment options.

How to identify MAC-PD patients with limited treatment options: an expert consensus https://bit.ly/3QwLQ8T.

Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions.

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 < 0.01], older [65.6 ± 18.2 vs. 60.3 ± 17.0; p < 0.01] and more frequently re-admitted [(16.2%) vs. (3.8%); p < 0.01). The rate of HYPO-FU was higher in the first year 23.6 per 100 individuals per year. After Cox regression analysis, the independent risk factors of HYPO-FU were diabetes [OR 2.12, IC 95% (1.48-3.04)], hypertension [OR 2.18, IC 95% (1.53-3.12)], heart failure [OR 3.34, IC 95% (1.72-6.48)] and invasive ventilation support requirement [OR: 2.38, IC 95% (1.63-3.50)]. To conclude, HYPO-FU was frequent in the first year after COVID-19 infection, and the risk was higher in older men with comorbidities, increasing rehospitalisation. Further studies aimed at evaluating the beneficial effects of correcting hyponatremia in these patients are warranted.

Efficacy of three benznidazole dosing strategies for adults living with chronic Chagas disease (MULTIBENZ): an international, randomised, double-blind, phase 2b trial.

BACKGROUND: Treatment with benznidazole for chronic Chagas disease is associated with low cure rates and substantial toxicity. We aimed to compare the parasitological efficacy and safety of 3 different benznidazole regimens in adult patients with chronic Chagas disease. METHODS: The MULTIBENZ trial was an international, randomised, double-blind, phase 2b trial performed in Argentina, Brazil, Colombia, and Spain. We included participants aged 18 years and older diagnosed with Chagas disease with two different serological tests and detectable T cruzi DNA by qPCR in blood. Previously treated people, pregnant women, and people with severe cardiac forms were excluded. Participants were randomly assigned 1:1:1, using a balanced block randomisation scheme stratified by country, to receive benznidazole at three different doses: 300 mg/day for 60 days (control group), 150 mg/day for 60 days (low dose group), or 400 mg/day for 15 days (short treatment group). The primary outcome was the proportion of patients with a sustained parasitological negativity by qPCR during a follow-up period of 12 months. The primary safety outcome was the proportion of people who permanently discontinued the treatment. Both primary efficacy analysis and primary safety analysis were done in the intention-to-treat population. The trial is registered with EudraCT, 2016-003789-21, and ClinicalTrials.gov, NCT03191162, and is completed. FINDINGS: From April 20, 2017, to Sept 20, 2020, 245 people were enrolled, and 234 were randomly assigned: 78 to the control group, 77 to the low dose group, and 79 to the short treatment group. Sustained parasitological negativity was observed in 42 (54%) of 78 participants in the control group, 47 (61%) of 77 in the low dose group, and 46 (58%) of 79 in the short treatment group. Odds ratios were 1·41 (95% CI 0·69-2·88; p=0·34) when comparing the low dose and control groups and 1·23 (0·61-2·50; p=0·55) when comparing short treatment and control groups. 177 participants (76%) had an adverse event: 62 (79%) in the control group, 56 (73%) in the low dose group, and 59 (77%) in the short treatment group. However, discontinuations were less frequent in the short treatment group compared with the control group (2 [2%] vs 11 [14%]; OR 0·20, 95% CI 0·04-0·95; p=0·044). INTERPRETATION: Participants had a similar parasitological responses. However, reducing the usual treatment from 8 weeks to 2 weeks might maintain the same response while facilitating adherence and increasing treatment coverage. These findings should be confirmed in a phase 3 clinical trial. FUNDING: European Community's 7th Framework Programme.

Epidemiological and clinical trends of imported strongyloidiasis in a referral international health unit, Barcelona, Spain: A 12-year period experience.

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.

A systematic review of potential biomarkers for bacterial burden and treatment efficacy assessment in TB platform-based clinical trials.

Adaptive platform trials can be more efficient than classic trials for developing new treatments. Moving from culture-based to simpler- or faster-to-measure biomarkers as efficacy surrogates may enhance this advantage. We performed a systematic review of treatment efficacy biomarkers in adults with tuberculosis. Platform trials can span different development phases. We grouped biomarkers as: α, bacterial load estimates used in phase 2a trials; ß, early and end-of treatment endpoints, phase 2b-c trials; γ, post-treatment or trial-level estimates, phase 2c-3 trials. We considered as analysis unit (biomarker entry) each combination of biomarker, predicted outcome, and their respective measurement times or intervals. Performance metrics included: sensitivity, specificity, area under the receiver-operator curve (AUC), and correlation measures, ,and classified as poor, promising, or good. Eighty-six studies included 22864 participants. From 1356 biomarker entries, 318 were reported with the performance metrics of interest, with 103 promising and 41 good predictors. Group results: α, mycobacterial RNA and Lipoarabinomannan in sputum, and host metabolites in urine; ß, mycobacterial RNA and host transcriptomic or cytokine signatures for early treatment response; γ, host transcriptomics for recurrence. A combination of biomarkers from different categories could help designing more efficient platform trials. Efforts to develop efficacy surrogates should be better coordinated.

Adherence and Toxicity during the Treatment of Latent Tuberculous Infection in a Referral Center in Spain.

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.

Impact, healthcare utilization and costs of travel-associated mosquito-borne diseases in international travellers: a prospective study.

BACKGROUND: International travellers frequently acquire infectious diseases whilst travelling, yet relatively little is known about the impact and economic burden of these illnesses on travellers. We conducted a prospective exploratory costing study on adult returning travellers with falciparum malaria, dengue, chikungunya or Zika virus. METHODS: Patients were recruited in eight Travel and Tropical Medicine clinics between June 2016 and March 2020 upon travellers' first contact with the health system in their country of residence. The patients were presented with a structured 52-question self-administered questionnaire after full recovery to collect information on patients' healthcare utilization and out-of-pocket costs both in the destination and home country, and about income and other financial losses due to the illness. RESULTS: A total of 134 patients participated in the study (malaria, 66; dengue, 51; chikungunya, 8; Zika virus, 9; all fully recovered; median age 40; range 18-72 years). Prior to travelling, 42% of patients reported procuring medical evacuation insurance. Across the four illnesses, only 7% of patients were hospitalized abroad compared with 61% at home. Similarly, 15% sought ambulatory services whilst abroad compared with 61% at home. The average direct out-of-pocket hospitalization cost in the destination country (USD $2236; range: $108-$5160) was higher than the direct out-of-pocket ambulatory cost in the destination country (USD $327; range: $0-$1560), the direct out-of-pocket hospitalization cost at home (USD $35; range: $0-$120) and the direct out-of-pocket ambulatory costs at home (US$45; range: $0-$192). Respondents with dengue or malaria lost a median of USD $570 (Interquartile range [IQR] 240-1140) and USD $240 (IQR 0-600), respectively, due to their illness, whilst those with chikungunya and Zika virus lost a median of USD $2400 (IQR 1200-3600) and USD $1500 (IQR 510-2625), respectively. CONCLUSION: Travellers often incur significant costs due to travel-acquired diseases. Further research into the economic impact of these diseases on travellers should be conducted.

Rickettsioses imported by travellers and migrants to Spain attended in the +Redivi network, 2009-2020.

BACKGROUND: Rickettsioses are emerging zoonotic diseases with worldwide prevalence, recognized as a cause of imported fever in travellers and migrants. Our objective is to describe the microbiological, clinical and epidemiological characteristics of imported rickettsioses in travellers and migrants included in a Spanish collaborative network database. METHODS: This multicentre retrospective observational study was nested in +Redivi, the Cooperative Network for the Study of Infections Imported by Immigrants and Travellers. We asked collaborating centres for microbiological, clinical and epidemiological data on the rickettsiosis cases from the inception of the network in 2009 to December 2020. RESULTS: Fifty-four cases of imported rickettsioses were included; 35 (64.8%) patients were men, and the median age was 37 years (interquartile range 26, 51.2). Only 7.4% of patients were travellers visiting friends and relatives, and 5.6% were migrants. The most frequent travel destination (38.9%) was South Africa, and 90.7% engaged in a high-risk activity. Twenty-seven patients (50.0%) started presenting symptoms after their return to Spain. The most frequent symptoms were febrile syndrome (55.6%) and cutaneous manifestations (27.8%). Most diagnoses (63.0%) were confirmed by serology. Only a few cases (9.3%) required hospitalization. All participants had a full recovery. CONCLUSIONS: Clinicians should suspect rickettsial diseases in travellers coming from high-risk areas, especially Southern Africa, who have engaged in activities in rural areas and natural parks. Doxycycline should be considered in the empiric treatment of imported fever of travellers coming from those areas or who have engaged in high-risk activities. There is a need to improve access to molecular diagnosis of rickettsiosis in Spain.

Community engagement in tuberculosis research: the EU-Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) experience.

OBJECTIVES: Community representatives are key to ensuring that tuberculosis (TB) research is relevant, culturally sensitive, and appropriate. For all trials (new drugs or treatment regimens, diagnostics, or vaccines) this can result in improvement of recruitment, retention, and adherence to the trial schedule. The early engagement of the community will, later in time, support the process of implementation of new policies designed for successful products. We aim at developing a structured protocol for the early engagement of TB community representatives developed in the context of the EU-Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. DESIGN: The EU-PEARL Innovative Medicine Initiative 2 (IMI2) project TB work package has developed a community engagement (CE) framework to ensure fair and efficient participation of the community in the design and implementation of TB clinical platform trials. RESULTS: We showed that early engagement of the EU-PEARL community advisory board highly contributes to the process of development of a community-acceptable Master Protocol Trial and Intervention-Specific Appendixes. We identified capacity building and training as major gaps in advancing CE in the TB field. CONCLUSION: Developing strategies to address these needs can contribute to preventing tokenism and increase the acceptability and appropriateness of TB research.

Time to sputum conversion in patients with pulmonary tuberculosis: A score to estimate the infectious period.

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.