PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19.

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.

A strategy for scaling up access to comprehensive care in adults with Chagas disease in endemic countries: The Bolivian Chagas Platform.

BACKGROUND: Bolivia has the highest prevalence of Chagas disease (CD) in the world (6.1%), with more than 607,186 people with Trypanosoma cruzi infection, most of them adults. In Bolivia CD has been declared a national priority. In 2009, the Chagas National Program (ChNP) had neither a protocol nor a clear directive for diagnosis and treatment of adults. Although programs had been implemented for congenital transmission and for acute cases, adults remained uncovered. Moreover, health professionals were not aware of treatment recommendations aimed at this population, and research on CD was limited; it was difficult to increase awareness of the disease, understand the challenges it presented, and adapt strategies to cope with it. Simultaneously, migratory flows that led Bolivian patients with CD to Spain and other European countries forced medical staff to look for solutions to an emerging problem. INTERVENTION: In this context, thanks to a Spanish international cooperation collaboration, the Bolivian platform for the comprehensive care of adults with CD was created in 2009. Based on the establishment of a vertical care system under the umbrella of ChNP general guidelines, six centres specialized in CD management were established in different epidemiological contexts. A common database, standardized clinical forms, a and a protocolized attention to adults patients, together with training activities for health professionals were essential for the model success. With the collaboration and knowledge transfer activities between endemic and non-endemic countries, the platform aims to provide care, train health professionals, and create the basis for a future expansion to the National Health System of a proven model of care for adults with CD. RESULTS: From 2010 to 2015, a total of 26,227 patients were attended by the Platform, 69% (18,316) were diagnosed with T. cruzi, 8,567 initiated anti-parasitic treatment, more than 1,616 health professionals were trained, and more than ten research projects developed. The project helped to increase the number of adults with CD diagnosed and treated, produce evidence-based clinical practice guidelines, and bring about changes in policy that will increase access to comprehensive care among adults with CD. The ChNP is now studying the Platform's health care model to adapt and implement it nationwide. CONCLUSIONS: This strategy provides a solution to unmet demands in the care of patients with CD, improving access to diagnosis and treatment. Further scaling up of diagnosis and treatment will be based on the expansion of the model of care to the NHS structures. Its sustainability will be ensured as it will build on existing local resources in Bolivia. Still human trained resources are scarce and the high staff turnover in Bolivia is a limitation of the model. Nevertheless, in a preliminary two-years-experience of scaling up this model, this limitations have been locally solved together with the health local authorities.

Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling.

Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life-because both mutant and wild-type receptors are expressed-and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.

Bed rest or ambulation in the initial treatment of patients with acute deep vein thrombosis or pulmonary embolism: findings from the RIETE registry.

BACKGROUND: Traditionally, many patients with acute deep vein thrombosis (DVT) are treated not only by anticoagulation therapy but additionally by strict bed rest, which is aimed at reducing the risk of pulmonary embolism (PE) events. However, this risk has not been subjected to empirical verification. PATIENTS AND METHODS: The Registro Informatizado de la Enfermedad TromboEmbólica is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute DVT or PE. In this analysis, the clinical characteristics, details of anticoagulant therapy, and clinical outcomes of enrolled patients with and without strict bed rest prescribed during the first 15 days were compared. Patients in whom ambulation was not possible were not included in this analysis. RESULTS: A total of 2,650 patients entered the study (DVT, 2,038 patients; PE, 612 patients). Of these patients, 1,050 DVT patients (52%) and 385 PE patients (63%) were prescribed strict bed rest. New events of symptomatic, objectively confirmed PE developed during the 15-day study period in 11 patients with DVT (0.5%) and 4 patients with PE (0.7%). Five of these 15 patients (33%) died as a result of their PE. Age < 65 years (odds ratio [OR], 3.1; 95% confidence interval [CI], 0.98 to 11) and cancer (OR, 3.0; 95% CI, 0.98 to 9.1) were associated with an increased rate of new PEs. There were not significant differences between bedridden and ambulant patients in terms of new PE events, fatal PE, or bleeding complications. CONCLUSIONS: Our findings confirm those from previous reports suggesting that bed rest has no influence on the risk of developing PE among patients with acute DVT of the lower limbs. In addition, our findings show for the first time the lack of influence of bed rest even in patients presenting with acute submassive PE.

Plasma d-dimer levels correlate with outcomes in patients with community-acquired pneumonia.

STUDY OBJECTIVES: The aim of this study was to investigate the prognostic value of plasma d-dimer levels in patients with community-acquired pneumonia (CAP). DESIGN: Prospective observational study. SETTING: Hospital Lluis Alcanyis of Xativa, Spain. PATIENTS: Consecutive adult patients admitted to the hospital with CAP from January 2000 to October 2002. MEASUREMENTS AND RESULTS: A total of 302 patients were included. Plasma d-dimer was measured using an automated latex assay. The relationships between plasma d-dimer and prognostic variables included in the pneumonia severity index (PSI) were examined using univariate and multivariate linear and logistic regression analyses. d-Dimer levels were negative (ie, < 500 ng/mL) in 16.9% of the patients. In nonsurvivors, the d-dimer plasma level mean value was 3,786 ng/mL, while in survivors it was 1,609 ng/mL (p < 0.0001). A significant relationship was found between the presence of elevated d-dimer levels and the PSI and APACHE (acute physiology and chronic health evaluation) II score. Elevated d-dimer levels were associated with radiologic pneumonia extension. The d-dimer predictive value for mechanical ventilation therapy showed an area under the curve of 0.78 (95% confidence interval, 0.71 to 0.81). CONCLUSIONS: d-Dimer plasma levels could be useful for predicting clinical outcome in patients with CAP.

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer.

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding.

D-dimer levels correlate with mortality in patients with acute pulmonary embolism: Findings from the RIETE registry.

OBJECT: Few studies have addressed the prognostic implications of D-dimer in patients with pulmonary embolism. The aim of this study was to investigate the correlation between D-dimer levels and mortality in patients with pulmonary embolism. DESIGN: Observational study. SETTING: Hospitals participating in the Registro Informatizado de la Enfermedad Tromboembólica (RIETE). PATIENTS: A total of 588 consecutive patients with symptomatic pulmonary embolism who were included in the RIETE between March 2001 and December 2004. INTERVENTIONS: Quantitative D-dimer measurement was performed on admission using an automated latex agglutination test (IL Test D-dimer). All patients underwent clinical follow-up for 3 months. MEASUREMENTS AND MAIN RESULTS: Overall mortality rate was 10.5%. The cause of death was pulmonary embolism in 18 patients (3.0%), fatal bleeding in one patient (0.2%), and other causes in 43 patients (7.3%). There were 28 (4.8%) nonfatal venous thromboembolism recurrences and 35 (6.0%) nonfatal bleeding episodes. The incidence of D-dimer 500-2499 ng/mL, D-dimer 2500-4999 ng/mL, and D-dimer >or=5000 ng/mL was 47.8%, 26.0%, and 20.4%, respectively. Compared with patients with D-dimer 500-2499 ng/mL, the relative risk (odds ratio) of overall mortality was 1.91 (95% confidence interval 0.91-4.09) and 2.94 (95% confidence interval 1.42-6.25) in patients with D-dimer 2500-4999 ng/mL and D-dimer >or= 5000 ng/mL, respectively (p = .032). Patients with D-dimer >or=5000 ng/mL showed higher risk of death from fatal pulmonary embolism (odds ratio 4.4, 95% confidence interval 0.5-33.0) than death from other causes (odds ratio 2.1, 95% confidence interval 0.7-6.0). Elevated D-dimer levels were associated with more severe disease, as assessed by clinical features. CONCLUSIONS: In patients who present with pulmonary embolism, D-dimer concentration is an independent predictive factor associated with all-cause and pulmonary embolism-related death. D-dimer >or=5000 ng/mL occurs in about one in five patients and is associated with a 2.9-fold increased risk of overall mortality. These results suggest that D-dimer quantification could be a useful biomarker and help determine initial therapies.