External validation of the CHEDDAR score for suspected pulmonary embolism in patients with SARS-CoV-2 infection in an independent cohort.

The accuracy of the classic scores that help stratify the pretest clinical probability of pulmonary embolism (PE) in SARS-CoV-2 infection (COVID-19) is low. Therefore, to estimate the risk of PE in these patients, a new set of guidelines must be established. The recently published CHEDDAR score proposes a new diagnostic strategy to reduce the use of computed tomography pulmonary angiography (CTPA) in non-critically ill SARS-COV-2 patients with suspected PE. According to the nomogram, patients are segregated into low-risk (< 182 points) or high-risk (≥ 182 points) based on the best cut-off value to discard PE in the original cohort. We aimed to externally validate this diagnostic strategy in an independent cohort. We analyzed data from two retrospective cohorts of hospitalized non-critically ill COVID-19 patients who underwent a CTPA due to suspicion for PE. CHEDDAR score was applied. As per the CHEDDAR nomogram, patients were classified as having a low or high clinical pre-test probability. Of the 270 patients included, 69 (25.5%) had PE. Applying the CHEDDAR score, 182 (67.4%) patients could have had PE excluded without imaging. Among 58 patients classified as having high clinical pre-test probability, 39 (67.2%) had PE. Sensitivity, specificity, positive and negative predictive values, and AUC were 56%, 90%, 67%, 85%, and 0.783 (95% CI 0.71-0.85), respectively. We provide external validation of the CHEDDAR score in an independent cohort. Even though the CHEDDAR score showed good discrimination capacity, caution is required in patients classified as having low clinical pre-test probability with a D-dimer value > 3000 ng/mL, and a RALE score ≥ 4.

Prediction of Venous Thromboembolism in Patients With Cancer Using Machine Learning Approaches: A Systematic Review and Meta-Analysis.

PURPOSE: Recent studies have suggested that machine learning (ML) could be used to predict venous thromboembolism (VTE) in cancer patients with high accuracy. METHODS: We aimed to evaluate the performance of ML in predicting VTE events in patients with cancer. PubMed, Web of Science, and EMBASE to identify studies were searched. RESULTS: Seven studies involving 12,249 patients with cancer were included. The combined results of the different ML models demonstrated good accuracy in the prediction of VTE. In the training set, the global pooled sensitivity was 0.87, the global pooled specificity was 0.87, and the AUC was 0.91, and in the test set 0.65, 0.84, and 0.80, respectively. CONCLUSION: The prediction ML models showed good performance to predict VTE. External validation to determine the result's reproducibility is necessary.

Clinical prediction model for pulmonary thrombosis diagnosis in hospitalized patients with SARS-CoV-2 infection.

Background and Aim: We aimed to develop a clinical prediction model for pulmonary thrombosis (PT) diagnosis in hospitalized COVID-19 patients. Methods: Non-intensive care unit hospitalized COVID-19 patients who underwent a computed tomography pulmonary angiogram (CTPA) for suspected PT were included in the study. Demographic, clinical, analytical, and radiological variables as potential factors associated with the presence of PT were selected. Multivariable Cox regression analysis to develop a score for estimating the pre-test probability of PT was performed. The score was internally validated by bootstrap analysis. Results: Among the 271 patients who underwent a CTPA, 132 patients (48.7%) had PT. Heart rate >100 bpm (OR = 4.63 [95% CI: 2.30-9.34]; P < 0.001), respiratory rate >22 bpm (OR = 5.21 [95% CI: 2.00-13.54]; P < 0.001), RALE score ≥4 (OR = 3.24 [95% CI: 1.66-6.32]; P < 0.001), C-reactive protein (CRP) >100 mg/L (OR = 2.10 [95% CI: 0.95-4.63]; P = 0.067), and D-dimer >3.000 ng/mL (OR = 6.86 [95% CI: 3.54-13.28]; P < 0.001) at the time of suspected PT were independent predictors of thrombosis. Using these variables, we constructed a nomogram (CRP, Heart rate, D-dimer, RALE score, and respiratory rate [CHEDDAR score]) for estimating the pre-test probability of PT. The score showed a high predictive accuracy (area under the receiver-operating characteristics curve = 0.877; 95% CI: 0.83-0.92). A score lower than 182 points on the nomogram confers a low probability for PT with a negative predictive value of 92%. Conclusions: CHEDDAR score can be used to estimate the pre-test probability of PT in hospitalized COVID-19 patients outside the intensive care unit. Relevance for Patients: Developing a new clinical prediction model for PT diagnosis in COVID-19 may help in the triage of patients, and limit unnecessary exposure to radiation and the risk of nephrotoxicity due to iodinated contrast.

Baricitinib or imatinib in hospitalized COVID-19 patients: Results from COVINIB, an exploratory randomized clinical trial.

Baricitinib and imatinib are considered therapies for coronavirus disease 2019 (COVID-19), but their ultimate clinical impact remains to be elucidated, so our objective is to determine whether these kinase inhibitors provide benefit when added to standard care in hospitalized COVID-19 patients. Phase-2, open-label, randomized trial with a pick-the-winner design conducted from September 2020 to June 2021 in a single Spanish center. Hospitalized adults with COVID-19 pneumonia and a symptom duration ≤10 days were assigned to 3 arms: imatinib (400 mg qd, 7 days) plus standard-care, baricitinib (4 mg qd, 7 days) plus standard-care, or standard-care alone. Primary outcome was time to clinical improvement (discharge alive or a reduction of 2 points in an ordinal scale of clinical status) compared on a day-by-day basis to identify differences ≥15% between the most and least favorable groups. Secondary outcomes included oxygenation and ventilatory support requirements, additional therapies administered, all-cause mortality, and safety. One hundred and sixty-five patients analyzed. Predefined criteria for selection of the most advantageous arm were met for baricitinib, but not for imatinib. However, no statistically significant differences were observed in formal analysis, but a trend toward better results in patients receiving baricitinib was found compared to standard care alone (hazard ratio [HR] for clinical improvement: 1.41, 95% confidence intervals [CI]: 0.96-2.06; HR for discontinuing oxygen: 1.46, 95% CI: 0.94-2.28). No differences were found regarding additional therapies administered or safety. Baricitinib plus standard care showed better results for hospitalized COVID-19 patients, being the most advantageous therapeutic strategy among those proposed in this exploratory clinical trial.

Trends in imported malaria during the COVID-19 pandemic, Spain (+Redivi Collaborative Network).

INTRODUCTION: The COVID-19 pandemic has caused disruptions in prevention and management strategies for malaria globally. Currently, data analysing trends in travel-related infections during the pandemic years are scarce. The objective of this analysis was to describe the epidemiological and clinical characteristics of patients with imported malaria within the +Redivi network in Spain, focusing on yearly trends from pre-pandemic years to date. METHODS: Cases recorded in +Redivi from October 2009 to December 2021 were analysed and patients with a diagnosis of malaria (standard diagnostic methods using thick/thin peripheral blood smears, with/without a malaria rapid diagnostic test and/or Plasmodium spp. polymerase chain reaction) were identified. The total number of malaria cases, cases according to type of patient and severe cases, per year, were analysed. RESULTS: In total, 1751 cases of malaria (1751/26 601, 6.6%) were identified. The majority occurred in males (1041, 59.5%), median age was 36.3 (interquartile range: 27-44.7) years and most occurred in visiting friends and relatives (VFR)-immigrants (872, 49.8%). Most infections were acquired in sub-Saharan Africa (1.660, 94.8%) and were due to Plasmodium falciparum (81.3%). There were 64 cases of severe malaria (3.7%) and 4 patients died (0.2% mortality, all in pre-pandemic years). A significant increase in cases of severe malaria was observed during the study period (P < 0.001) (attributable to the increase in 2021). There were 16/93 severe cases in 2021 (17.2%), all due to Plasmodium falciparum, (compared with ≤ 5% in previous years), which mainly occurred in travellers and VFR-immigrants (10/16, 62.5% and 5/16, 31.3%, respectively). CONCLUSIONS: After an initial decline associated with travel restrictions due to the ongoing COVID-19 pandemic, an increase in imported malaria and a significant increase in cases of severe malaria was observed. Patients with imported malaria may present and/or be diagnosed late during this public health crisis and health care professionals should be alerted to the recent increase in severe cases.

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.

Latent and active tuberculosis infections in migrants and travellers: A retrospective analysis from the Spanish +REDIVI collaborative network.

BACKGROUND: Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide. We analysed active and latent TB infections (LTBI) from the Spanish Network for the Study of Imported Infectious Diseases by Travellers and Immigrants (+REDIVI). METHODS: Observational, retrospective, multicentre study of TB and LTBI registered in the +REDIVI network from October 2009 to December 2016. RESULTS: Of 1008 cases of LTBI, 884 (87.7%) were immigrants; 93 (4.5%), immigrants visiting friends and relatives (VFR); 2 (0.9%), VFR-travellers; and 29 (1.1%), travellers. Absolute (N = 157 vs. N = 75) and relative (12.5% vs. 5.9%) frequency decreased over the study period (p = 0.003). Median time to diagnosis was 24.6 months (females 50.3 vs males 11.9; p < 0.001). Of 448 TB cases, 405 (90.4%) were in immigrants; 30 (6.7%), VFR-immigrants; 6 (1.3%), VFR-travellers; and 7 (1.6%), travellers. Median time to diagnosis was 62.5 months (females 86.6 vs males 70.1; p = 0.0075). There were 8 multidrug resistant TB cases and 1 extensively drug resistant case of TB, all in immigrants. CONCLUSION: TB was frequently diagnosed more than 5 years after arrival in Spain. Screening programmes for TB and LTBI in immigrants should be considered beyond this time point. Women showed a higher diagnostic delay for both latent and active TB.

Blood stream infections associated with central and peripheral venous catheters.

BACKGROUND: The purposes of this study were to determine the incidence of central and peripheral venous catheter-related bacteraemias, the relationship between the suspected and final confirmed bacteraemia origins, and the differences in microbiological, epidemiological, clinical, and analytical characteristics between the groups, including evolution to death. METHODS: This was a 7-year descriptive retrospective populational study of all bloodstream infections, comparing central (CB) and peripheral (PB) venous catheter-related bacteraemias in patients older than 15 years. RESULTS: In all, 285 catheter-related bacteraemia patients, 220 with CBs (77.19%) and 65 with PBs (22.81%), were analysed among 1866 cases with bloodstream infections. The cumulative incidence per 1000 patients-day of hospital stay was 0.36 for CB and 0.106 for PB. In terms of the suspected origin, there was less accuracy in diagnosing catheter-related bloodstream infections (68. 2%) than those of other origins (78. 4%), p <  0.001. The accuracy was greater for PB (75%) than for CB (66. 2%), Coagulase-negative staphylococci were the most frequent microorganisms in both groups but occurred 1.57 times more frequently in CB (64.1%/40.6%) (p = 0.004), while Staphylococcus aureus (23. 4%/9.5%) (p = 0.02) and Enterobacteriae species (15.6%/6. 3%) (p = 0.003) were 2.5 times more frequent in PB. The CB patients stayed at the hospital for an average of 7.44 days longer than did the PB patients; more CB patients had active neoplasia (70. 4%/32.8%), more had surgery in the previous week (29. 2%/8. 3%), and fewer received adequate empirical treatment (53.9%/ 62.5%). Catheter was not removed in 8. 2% of CB and 3.7% of PB. On the other hand, the CB and PB patients had similar Pitt scores at blood extraction (median 0.89 versus 0.84 points, respectively; p = 0.8) and similar survival rates at hospital discharge (91.1% versus 90. 2%; p = 0.81). CONCLUSIONS: Central catheters were more frequent sources of bacteraemias than were peripheral catheters. There were important differences in the microbiological aetiology as well. PB patients received correct empirical antibiotic treatment more frequently and had a higher initial rate of correct determination of the suspected source of bacteraemia. Differences in the microbiological aetiology and empirical antibiotic treatment received, and probably catheter removal and time to catheter removal could explain why CB and PB patients had similar survival rates .

Diagnostic model of visceral leishmaniasis based on bone marrow findings. Study of patients with clinical suspicion in which the parasite is not observed.

BACKGROUND: Visceral Leishmaniasis (VL) is a serious protozoal disease endemic in diverse areas, including the southern area of Madrid (Spain), where an outbreak was detected in 2009. The objective of this work is to analyze bone marrow alterations in VL patients and elaborate a diagnostic model with the aim to improve the early detection of this disease. The usual diagnostic methods, as the observation of the parasite on a bone marrow aspirate, have frequent false negatives, and the high sensitivity methods, as PCR and ELISA, are delayed or are not always available. METHODS: This observational study evaluated bone marrow parameters of adult patients with clinical suspicion of VL, in which a bone marrow aspiration was performed but Leishmania was not directly observed, during the period 2009-2014. The patients finally diagnosed of VL by other methods (VL group, n=41), and the patients in which the VL was not diagnosed (non-VL group, n=20) were compared. A multivariant model was elaborated and externally validated. RESULTS: The final multivariant model includes percentage of myeloid series, percentage of plasma cells and quantification of megakaryocytes in the bone marrow, with an area under the ROC curve of 0.87 (0.78-0.96). The model performed well in the external validation. CONCLUSION: In cases of VL suspicion and when the parasite is not observed in the bone marrow aspiration, the proposed model could be useful in discriminating between patients with and without VL, allowing to take a therapeutic decision while awaiting the definitive diagnosis.

Clinical aspects of visceral leishmaniasis caused by L. infantum in adults. Ten years of experience of the largest outbreak in Europe: what have we learned?

BACKGROUND: An outbreak of leishmaniasis caused by Leishmania infantum was declared in the southwest of the Madrid region (Spain) in June 2009. This provided a unique opportunity to compare the management of visceral leishmaniasis (VL) in immunocompetent adults (IC-VL), patients with HIV (HIV-VL) and patients receiving immunosuppressants (IS-VL). METHODS: A cohort of adults with VL, all admitted to the Hospital Universitario de Fuenlabrada between June 2009 and June 2018, were monitored in this observational study, recording their personal, epidemiological, analytical, diagnostic, treatment and outcome variables. RESULTS: The study population was made up of 111 patients with VL (10% HIV-VL, 14% IS-VL, 76% IC-VL). Seventy-one percent of the patients were male; the mean age was 45 years (55 years for the IS-VL patients, P = 0.017). Fifty-four percent of the IC-VL patients were of sub-Saharan origin (P = 0.001). Fever was experienced by 98% of the IC-VL patients vs 73% of the LV-HIV patients (P = 0.003). Plasma ferritin was > 1000 ng/ml in 77% of the IC-VL patients vs 17% of the LV-HIV patients (P = 0.007). Forty-two percent of patients fulfilled the criteria for haemophagocytic lymphohistiocytosis. RDT (rK39-ICT) serological analysis returned sensitivity and specificity values of 45% and 99%, respectively, and ELISA/iIFAT returned 96% and 89%, respectively, with no differences in this respect between patient groups. Fourteen (13.0%) patients with VL experienced treatment failure, eight of whom were in the IC-VL group. Treatment with < 21 mg/kg (total) liposomal amphotericin B (LAB) was associated with treatment failure in the IC-VL patients [P = 0.002 (OR: 14.7; 95% CI: 2.6-83.3)]. CONCLUSIONS: IS-VL was more common than HIV-VL; the lack of experience in dealing with IS-VL is a challenge that needs to be met. The clinical features of the patients in all groups were similar, although the HIV-VL patients experienced less fever and had lower plasma ferritin concentrations. RDT (rK39-ICT) analysis returned a good specificity value but a much poorer sensitivity value than reported in other scenarios. The patients with HIV-VL, IS-VL and IC-VL returned similar serological results. Current guidelines for treatment seem appropriate, but the doses of LAB required to treat patients with HIV-VL and IS-VL are poorly defined.

Prevalence of submicroscopic malaria infection in immigrants living in Spain.

BACKGROUND: The importance of submicroscopic malaria infections in high-transmission areas could contribute to maintain the parasite cycle. Regarding non-endemic areas, its importance remains barely understood because parasitaemia in these afebrile patients is usually below the detection limits for microscopy, hence molecular techniques are often needed for its diagnosis. In addition to this, the lack of standardized protocols for the screening of submicroscopic malaria in immigrants from endemic areas may underestimate the infection with Plasmodium spp. The aim of this study was to assess the prevalence of submicroscopic malaria in afebrile immigrants living in a non-endemic area. METHODS: A prospective, observational, multicentre study was conducted. Afebrile immigrants were included, microscopic observation of Giemsa-stained thin and thick blood smears, and two different molecular techniques detecting Plasmodium spp. were performed. Patients with submicroscopic malaria were defined as patients with negative blood smears and detection of DNA of Plasmodium spp. with one or both molecular techniques. Demographic, clinical, analytical and microbiological features were recorded and univariate analysis by subgroups was carried out with STATA v15. RESULTS: A total of 244 afebrile immigrants were included in the study. Of them, 14 had a submicroscopic malaria infection, yielding a prevalence of 5.7% (95% confidence interval 3.45-9.40). In 71.4% of the positive PCR/negative microscopy cases, Plasmodium falciparum alone was the main detected species (10 out of the 14 patients) and in 4 cases (28.6%) Plasmodium vivax or Plasmodium ovale were detected. One patient had a mixed infection including three different species. CONCLUSIONS: The prevalence of submicroscopic malaria in afebrile immigrants was similar to that previously described in Spain. Plasmodium vivax and P. ovale were detected in almost a third of the submicroscopic infections. Screening protocols for afebrile immigrants with molecular techniques could be useful for a proper management of these patients.

Asymptomatic immune responders to Leishmania among HIV positive patients.

Concomitant infection with human immunodeficiency virus (HIV) and the Leishmania parasite is a growing public health problem, the result of the former spreading to areas where the latter is endemic. Leishmania infection is usually asymptomatic in immunocompetent individuals, but the proportion of HIV+ individuals in contact with the parasite who remain asymptomatic is not known. The aim of the present work was to examine the use of cytokine release assays in the detection of asymptomatic immune responders to Leishmania among HIV+ patients with no previous leishmaniasis or current symptomatology. Eighty two HIV+ patients (all from Fuenlabrada, Madrid, Spain, where a leishmaniasis outbreak occurred in 2009) were examined for Leishmania infantum infection using molecular and humoral response-based methods. None returned a positive molecular or serological result for the parasite. Thirteen subjects showed a positive lymphoproliferative response to soluble Leishmania antigen (SLA), although the mean CD4+ T lymphocyte counts of these patients was below the normal range. Stimulation of peripheral blood mononuclear cells (PBMC) or whole blood with SLA (the lymphoproliferative assay and whole blood assay respectively), led to the production of specific cytokines and chemokines. Thus, despite being immunocompromised, HIV+ patients can maintain a Th1-type cellular response to Leishmania. In addition, cytokine release assays would appear to be useful tools for detecting these individuals via the identification of IFN-γ in the supernatants of SLA-stimulated PBMC, and of IFN-γ, MIG and IL-2 in SLA-stimulated whole blood. These biomarkers appear to be 100% reliable for detecting asymptomatic immune responders to Leishmania among HIV+ patients.

Clinicoepidemiological characteristics of viral hepatitis in migrants and travellers of the +Redivi network.

BACKGROUND: Continuous growth of mobile populations has influenced the global epidemiology of infectious diseases, including chronic and acute viral hepatitis. METHOD: A prospective observational multicentre study was performed in a Spanish network of imported infections. Viral hepatitis cases from January 2009 to September 2017 were included. RESULTS: Of 14,546 records, 723 (4.97%) had imported viral hepatitis, including 48 (6.64%) acute cases and 675 (93.36%) chronic cases. Of the 48 acute cases, 31 were travellers and immigrants returning from visiting friends or relatives (VFR), while 19 (61%) were acute Hepatitis A or Hepatitis B. Only 18.2% of VFR immigrants and 35% of travellers received pre-travel advice. Acute hepatitis was more frequent in VFR immigrants (AOR 2.59, CI95% 1.20-5.60) and travellers (AOR 2.83, CI95% 1.46-5.50) than immigrants. Of the 675 Chronic cases, 570 were immigrants, and 439 (77%) had chronic Hepatitis B. Chronic hepatitis was more frequent in immigrants (AOR 20.22, CI95% 11.64-35.13) and VFR immigrants (AOR 11.12, CI95% 6.20-19.94) than travellers. CONCLUSIONS: Chronic viral hepatitis was typical of immigrants, acute viral hepatitis was common among travellers, and VFR immigrants had mixed risk. Improving pre-travel consultation and screening of immigrants may contribute to preventing new cases of viral hepatitis and avoiding community transmission.